Heterocyclic oxime compounds

ABSTRACT

The invention relates to compounds of formula (I) and salts thereof: 
     
       
         
         
             
             
         
       
     
     wherein the substituents are as defined in the specification; a compound of formula (I) for use in the treatment of the human or animal body, in particular with regard to c-Met tyrosine kinase mediated diseases or conditions; the use of a compound of formula (I) for manufacturing a medicament for the treatment of such diseases; pharmaceutical compositions comprising a compound of the formula (I), optionally in the presence of a combination partner, and processes for the preparation of a compound of formula (I).

This application claims benefit under 35 U.S.C. §119(a)-(d) or (f) or365(b) of U.S. Provisional Application 61/235,440, filed 20 Aug. 2009,and Chinese applications PCT/CN10/071978, filed 21 Apr. 2010, andPCT/CN10/074089, filed 18 Jun. 2010, the contents of which areincorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

The Hepatocyte Growth Factor Receptor, herein referred to as c-Met, is areceptor tyrosine kinase that has been shown to be over-expressed and/orgenetically altered in a variety of malignancies, specifically, geneamplification, and a number of c-Met mutations are found in varioussolid tumors, see e.g. WO2007/126799. Further, the receptor tyrosinekinase c-Met is involved in the processes of migration, invasion andmorphogenesis that accompany embryogenesis and tissue regeneration.C-Met is also involved in the process of metastasis. Several lines ofevidence have indicated that c-Met plays a role in tumor pathogenesis.Gain of function germ line mutations in c-Met is associated withdevelopment of hereditary papillary renal cell carcinoma (PRCC).Amplification or mutations in c-Met have also been reported in sporadicforms of PRCC, in head and neck squamous cell carcinoma, in gastriccarcinoma, in pancreatic carcinoma and in lung cancer. Such alterationshave been shown in selected instances to confer dependence of the tumoron c-Met and/or resistance to other targeted therapies. Elevated levelsof c-Met, together with its unique ligand HGF/SF, are observed at highfrequency in multiple clinically relevant tumors. A correlation betweenincreased expression and disease progression, metastases and patientmortality has been reported in several cancers, including bladder,breast, squamous cell carcinoma and gastric carcinoma as well asleiomyosarcoma and glioblastoma.

WO 2008/008539 discloses certain fused heterocyclic derivatives whichare useful in the treatment of HGF mediated diseases. WO 2007/013673discloses fused heterocyclic derivatives as Lck inhibitors which areuseful as immunosuppressive agents. EP0490587 discloses certainpyrazolopyrimidines which are useful as angiotensin II antagonists. Thedisclosures of the publications cited in this specification are hereinincorporated by reference.

BRIEF SUMMARY OF THE INVENTION

The invention relates to bicyclic compounds of formula (I) and saltsthereof, the uses of such compounds to treat the human or animal body,in particular with regard to a proliferative disease, pharmaceuticalcompositions comprising such compounds, combinations comprising acompound of formula (I), and processes for the preparation of suchcompounds.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1. X-ray diffractogram of Example 53S amorphous form.

FIG. 2. X-ray diffractogram of Example 53S crystalline form I.

FIG. 3. X-ray diffractogram of Example 53S crystalline form II.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a compound of the formula (I)

wherein

Y is C or N; X is CH or N; B is CH or N;

A is a ring;such that when X is CH and B is N, ring A is ring Ai or ring Aii;

when X is N and B is N, ring A is Aiii;

and when X is N and B is N, or X is N and B is CH, ring A is Ai;

R¹ is a group selected from i, ii and iii:

wherein R⁵ is heteroaryl¹,R⁶ is hydrogen, deuterium, OH, methyl or halo;R⁷ is hydrogen, deuterium, halo, or (C₁-C₃)alkyl, wherein said(C₁-C₃)alkyl is optionally substituted by one or more substituentsindependently selected from OH and halo;or R⁶ and R⁷, together with the carbon to which they are attached, formcyclopropyl;n is 0, 1 or 2;R² is hydrogen, NH₂, or (C₁-C₄)alkyl, wherein said (C₁-C₄)alkyl isoptionally substituted by one or more substituents independentlyselected from OH, NH₃ and halo;

and R³ is

-   -   (C₁-C₆)alkyl, wherein said (C₁-C₆)alkyl is optionally        substituted by one or more substituents independently selected        from halo, hydroxy and (C₁-C₃)alkoxy,    -   heterocyclyl¹    -   phenyl, wherein said phenyl is optionally substituted by one or        more substituents independently selected from halo, hydroxy,        (C₁-C₃)alkyl and (C₁-C₃)alkoxy, wherein said (C₁-C₃)alkyl and        (C₁-C₃)alkoxy are each optionally substituted by one or more        halo substituents,    -   —CH₂-heterocyclyl¹    -   —CH₂-phenyl, wherein the phenyl of said —CH₂-phenyl is        optionally substituted by one or more substituents independently        selected from halo, hydroxy, (C₁-C₃)alkyl and (C₁-C₃)alkoxy,        wherein said (C₁-C₃)alkyl and (C₁-C₃)alkoxy are each optionally        substituted by one or more halo substituents,    -   (C₁-C₄)alkylCO₂(C₁-C₂)alkyl,    -   (C₀-C₄)alkylCONH₂,    -   (C₁-C₄)alkylNH₂,    -   (C₁-C₄)alkylNHCONH₂,    -   (C₁-C₄)alkylCO₂H,    -   (C₁-C₄)alkylNHCO₂CH₃,    -   —(C₀-C₄)alkyl(C₃-C₆)cycloalkyl or        —(C₀-C₄)alkyl(C₄-C₆)cycloalkenyl, or    -   Hydrogen,        or a pharmaceutically acceptable salt thereof.

It is an aim of the present invention to provide further compounds thatmodulate, and in particular inhibit, c-Met. It has now been found thatthe compounds of the formula (I) described herein are inhibitors ofc-Met and have a number of therapeutic applications. For example, thecompounds of formula (I) are suitable for use in the treatment ofdiseases dependent on c-Met activity, especially solid tumors ormetastasis derived therefrom. Through the inhibition of c-Met, compoundsof the invention also have utility as anti-inflammatory agents, forexample for the treatment of an inflammatory condition which is due toan infection.

Preferably, the compounds of the invention are metabolically stable, arenon-toxic and demonstrate few side-effects. In addition, preferredcompounds of the invention exist in a physical form that is stable,non-hygroscopic and easily formulated. One aspect of the invention isdirected to compounds of formula (I) having an activity that is superiorto the activity of compounds of the prior art, or other similarcompounds. Another aspect of the invention is directed to compounds offormula (I) having good kinase selectivity. Preferred compounds of theinvention posses favourable pharmacokinetic properties, such as goodin-vivo exposure and/or solubility.

The following general definitions shall apply in this specification,unless otherwise specified:

A “compound of the invention”, or “compounds of the invention”, or “acompound of the present invention” means a compound or compounds offormula (I) as described herein.

As used herein, the terms “including”, “containing” and “comprising” areused herein in their open, non-limiting sense.

Where the plural form (e.g. compounds, salts) is used, this includes thesingular (e.g. a single compound, a single salt). “A compound” does notexclude that (e.g. in a pharmaceutical formulation) more than onecompound of the formula (I) (or a salt thereof) is present.

“Treatment” includes prophylactic (preventive) and therapeutic treatmentas well as the delay of progression of a disease, disorder or condition.

Any non-cyclic carbon containing group or moiety with more than 1 carbonatom is straight-chain or branched. “Alkyl” refers to a straight-chainor branched-chain alkyl group. For example, (C₁-C₄)alkyl includesmethyl, ethyl, n- or iso-propyl, and n-, iso-, sec- or tert-butyl.

Heteroaryl¹ is a 9- or 10-membered, unsaturated or partially unsaturatedbicyclic group comprising 1, 2, 3 or 4 ring heteroatoms independentlyselected from N, O and S, wherein the total number of ring S atoms doesnot exceed 1, and the total number of ring O atoms does not exceed 1,wherein heteroaryl¹ is optionally substituted by one or moresubstituents, preferably 1, 2 or 3 substituents, independently selectedfrom:

-   -   halo,    -   OH,    -   (C₁-C₃)alkyl, said (C₁-C₃)alkyl being optionally substituted by        one or more substituents independently selected from OH and        halo,    -   heterocyclyl²,    -   —C(CH₃)═NO(C₁-C₃)alkyl, wherein the (C₁-C₃)alkyl of said        C(CH₃)═NO(C₁-C₃)alkyl is optionally substituted by one or more        substituents independently selected from OH and halo.

In another embodiment, heteroaryl¹ is optionally substituted by one ormore substituents, preferably 1, 2 or 3 substituents, independentlyselected from:

-   -   halo,    -   OH,    -   (C₁-C₃)alkyl, said (C₁-C₃)alkyl being optionally substituted by        one or more substituents independently selected from OH and        halo, and    -   —C(CH₃)═NO(C₁-C₃)alkyl, wherein the (C₁-C₃)alkyl of said        C(CH₃)═NO(C₁-C₃)alkyl is optionally substituted by one or more        substituents independently selected from OH and halo.

Specific examples of heteroaryl¹ include, but are not limited to,quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl,phthalazinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl,1,7-naphthyridinyl, 1,8-naphthyridinyl, 2,6-naphthyridinyl,2,7-naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl,pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl,pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl,pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl,pyrimido[4,5-d]pyrimidinyl, benzofuranyl, benzothiophenyl, indolyl,benzimidazolyl, benzoxazolyl, indazoyl, benzotriazolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl,pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl,imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl,pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3-c]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, isoindolyl,indazolyl, purinyl, indolizinyl, imidazo[1,2-a]pyridinyl,imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,pyrrolo[1,2-b]pyridazinyl and imidazo[1,2-c]pyrimidinyl, and thepartially saturated equivalents thereof.

“heteroaryl³” means a 9- or 10-membered, unsaturated or partiallyunsaturated bicyclic group comprising 1 or 2 ring N heteroatoms.Heteroaryl³ is optionally substituted by one or more substituentsindependently selected from:

-   -   halo,    -   OH,    -   (C₁-C₃)alkyl, wherein said (C₁-C₃)alkyl is optionally        substituted by one or more substituents independently selected        from OH and halo.    -   heterocyclyl², and    -   —C(CH₃)═NO(C₁-C₃)alkyl, wherein the (C₁-C₃)alkyl of said        C(CH₃)═NO(C₁-C₃)alkyl is optionally substituted by one or more        substituents independently selected from OH and halo,

In another embodiment, heteroaryl³ is optionally substituted by one ormore substituents independently selected from:

-   -   halo,    -   OH,    -   (C₁-C₃)alkyl, wherein said (C₁-C₃)alkyl is optionally        substituted by one or more substituents independently selected        from OH and halo, and    -   —C(CH₃)═NO(C₁-C₃)alkyl, wherein the (C₁-C₃)alkyl of said        C(CH₃)═NO(C₁-C₃)alkyl is optionally substituted by one or more        substituents independently selected from OH and halo.

Specific examples of heteroaryl³ include, but are not limited to,quinolinyl, isoquinolinyl, cinnolinyl, azaquinazolinyl, quinoxalinyl,phthalazinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl,1,7-naphthyridinyl, 1,8-naphthyridinyl, 2,6-naphthyridinyl,2,7-naphthyridinyl, indolyl, benzimidazolyl, indazolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl,pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, isoindolyl, indazolyl,indolininyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl,pyrazolo[1,5-a]pyridinyl and pyrrolo[1,2-b]pyridazinyl.

“heterocyclyl¹” means a 4, 5 or 6 membered saturated or partiallyunsaturated monocyclic group comprising 1 or 2 ring heteroatomsindependently selected from N, O and S. Heterocyclyl¹ is optionallysubstituted by CONH₂ or (C₁-C₃)alkyl. Specific examples of heterocyclyl¹include, but are not limited to, oxetanyl, thiatanyl, azetidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, 1,2,3,4-tetrahydropyridinyl,1,2,5,6-tetrahydropyridinyl, pyrrolidinyl, piperidinyl and piperazinyl.

“heterocyclyl²” means a 5 or 6 membered saturated, unsaturated orpartially unsaturated monocyclic group comprising 1, 2 or 3 ringheteroatoms independently selected from N, O and S, wherein the totalnumber of ring S atoms does not exceed 1, and the total number of ring Oatoms does not exceed 1. Heterocyclyl² is optionally substituted by(C₁-C₃)alkyl. Specific examples of heterocyclyl² include, but are notlimited to, tetrahydrofuranyl, tetrahydrothiophenyl,1,2,3,4-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl, pyrrolidinyl,piperidinyl, piperazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl,imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl,1,2,3-triazolyl, 1,3,4-triazolyl, 1-oxa-2,3-diazolyl,1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl,1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl,1-thia-3,4-diazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl and 2H-pyranyl.

“disease” as used herein includes a disorder or condition.

Halo means fluoro, chloro, bromo or iodo. In a particular embodiment ofthe invention, halo is fluoro or chloro. Preferably, halo is fluoro.

According to the disclosures herein, the compound of formula (I) isselected from any one of the following structures (Ia) to (Ie):

In an embodiment of the invention, there is provided a compound offormula (I) wherein

B is N; Y is C or N; X is CH or N;

such that when X is CH, ring A is ring Ai or ring Aii

when X is N, ring A is Aiii;

and when X is N and B is CH, ring A is Ai.

Such compounds have the structure (Ia), (Ib), (Ic) or (Ie) as disclosedherein.

In another embodiment of the invention, there is provided a compound offormula (I) wherein

B is N; Y is C or N; X is CH or N;

such that when X is CH, ring A is ring Ai or ring Aii

and when X is N, ring A is Aiii;

Such compounds have the structure (Ia), (Ib) or (Ic) as disclosed herein

In a particular embodiment of the invention there is provided a compoundhaving formula (Ib), wherein the substituents are as defined herein.

In another embodiment of the invention, R¹ is i or ii:

In a preferred embodiment of the invention, R¹ is i:

In another embodiment of the invention, R¹ is a group selected from i,ii and iii:

and R⁵ is heteroaryl³.

In another embodiment of the invention, R¹ is i:

and R⁵ is heteroaryl³.

In another embodiment of the invention, heteroaryl¹ and heteroaryl³ areeach optionally substituted by one or more substituents independentlyselected from halo, 4-methylpiperazin-1-yl, ethanoneO-(2-hydroxyethyl)oxime and (C₁-C₂)alkyl.

In a preferred embodiment of the invention, R⁵ is indazolyl orquinolinyl, each optionally substituted by one or more substituentsindependently selected from halo, (C₁-C₃)alkyl, 4-methylpiperazin-1-yland ethanone O-(2-hydroxyethyl)oxime. In particular, R⁵ is indazolyl orquinolinyl optionally substituted by one, two or three substituentsindependently selected from halo and (C₁-C₃)alkyl.

In a further preferred embodiment of the invention, R⁵ is indazolyloptionally substituted by one, two or three substituents independentlyselected from methyl and fluoro, or R⁵ is quinolinyl optionallysubstituted by one or two fluoro substituents.

In a particular embodiment of the invention, R⁵ is indazol-5-ylsubstituted at the 1 position by a methyl substituent and optionallyfurther substituted by one or two fluoro substituents, or R⁵ isquinolin-6-yl optionally substituted by one or two fluoro substituents.In an embodiment of the invention, said fluoro substituents are presentat the 5 and/or 7 positions of the quinolinyl group.

In a particular embodiment of the invention, R⁵ is quinolin-6-ylsubstituted by

-   -   heterocyclyl², or    -   —C(CH₃)═NO(C₁-C₃)alkyl, wherein the (C₁-C₃)alkyl of said        C(CH₃)═NO(C₁-C₃)alkyl is optionally substituted by one or more        substituents independently selected from OH and halo        wherein said heterocyclyl² and —C(CH₃)═NO(C₁-C₃)alkyl        substituents are present at the 3-position of the quinolinyl        group.

In a further embodiment, R⁵ is quinolin-6-yl substituted by3-(4-methylpiperazin-1-yl) or quinolin-6-yl substituted by 3-ethanoneO-(2-hydroxy-ethyl)oxime.

In a particular embodiment of the invention, R⁵ is7-fluoro-quinolin-6-yl, quinolin-6-yl, 5,7-difluoroquinolin-6-yl,1-methyl-1H-indazol-5-yl, 6-fluoro-1-methyl-1H-indazol-5-yl,4,6-difluoro-1-methyl-1H-indazol-5-yl, 5-Fluoroquinolin-6-yl,3-(4-methylpiperazin-1-yl)quinolin-6-yl or 6-quinolin-3-yl-ethanoneO-(2-hydroxy-ethyl)oxime.

In another embodiment of the invention, R⁶ is hydrogen, deuterium, OH orhalo, particularly hydrogen, deuterium or halo, and in a preferredembodiment, R⁶ is hydrogen.

In another embodiment of the invention, R⁷ is hydrogen, deuterium, halo,or methyl, wherein said methyl is optionally substituted by one or moresubstituents independently selected from OH and halo. In anotherembodiment of the invention R⁷ is hydrogen, deuterium, halo, or methyl.In a preferred embodiment, R⁷ is hydrogen or methyl, more preferablyhydrogen.

Where R¹ is i, and R⁶ and R⁷ are not both hydrogen, the compound offormula (I) contains an asymmetric carbon atom at R¹. Included withinthe scope of the invention is a compound of formula (I) containing the(R), or the (S) enantiomer of R¹i, or a mixture thereof. In a preferredembodiment of the invention there is provided a compound of formula (I)containing the (S) enantiomer of R¹i, or a mixture including the (S)enantiomer as a major component.

In a preferred embodiment of the invention n is 0.

In another embodiment of the invention, R² is hydrogen or methyl.Preferably, R² is methyl.

In another embodiment of the invention, R³ is selected from:

-   -   (C₁-C₆)alkyl, wherein said (C₁-C₆)alkyl is optionally        substituted by one or more substituents independently selected        from halo, hydroxy and (C₁-C₃)alkoxy,    -   heterocyclyl¹    -   phenyl, wherein said phenyl is optionally substituted by one or        more substituents independently selected from halo, hydroxy,        (C₁-C₃)alkyl and (C₁-C₃)alkoxy, wherein said (C₁-C₃)alkyl and        (C₁-C₃)alkoxy are each optionally substituted by one or more        halo substituents,    -   —CH₂-heterocyclyl¹    -   —CH₂-phenyl, wherein the phenyl of said —CH₂-phenyl is        optionally substituted by one or more substituents independently        selected from halo, hydroxy, (C₁-C₃)alkyl and (C₁-C₃)alkoxy,        wherein said (C₁-C₃)alkyl and (C₁-C₃)alkoxy are each optionally        substituted by one or more halo substituents,    -   (C₁-C₂)alkylCO₂(C₁-C₂)alkyl,    -   (C₀-C₂)alkylCONH₂,    -   (C₁-C₄)alkylNH₂,    -   (C₁-C₂)alkylNHCONH₂,    -   (C₁-C₂)alkylCO₂H,    -   (C₁-C₂)alkylNHCO₂CH₃, or    -   Hydrogen,

In another embodiment of the invention, R³ is selected from:

-   -   (C₁-C₄)alkyl, wherein said (C₁-C₄)alkyl is optionally        substituted by one or more substituents independently selected        from halo, hydroxy and methoxy,    -   pyrrolidinyl, optionally substituted by CONH₂,    -   piperidinyl,    -   phenyl, wherein said phenyl is optionally substituted by one or        more substituents independently selected from halo, hydroxy,        (C₁-C₃)alkyl and (C₁-C₃)alkoxy, wherein said (C₁-C₃)alkyl and        (C₁-C₃)alkoxy are each optionally substituted by one or more        halo substituents,    -   —CH₂-pyrrolidinyl, wherein said pyrrolidinyl is optionally        substituted by CONH₂,    -   —CH₂-piperidinyl,    -   —CH₂-phenyl, wherein the phenyl of said —CH₂-phenyl is        optionally substituted by one or more substituents independently        selected from halo, methyl and methoxy, wherein said methyl is        optionally substituted by one, two or three halo substituents,    -   (C₁-C₂)alkylCO₂(C₁-C₂)alkyl,    -   (C₀-C₂)alkylCONH₂,    -   (C₂-C₄)alkylNH₂,    -   (C₁-C₂)alkylNHCONH₂,    -   (C₁-C₂)alkylCO₂H,    -   oxetanyl    -   (C₁-C₂)alkylNHCO₂CH₃,    -   —CH₂—(C₃-C₆)cycloalkyl, and    -   hydrogen

In a particular embodiment of the invention, R³ is ethyl, methyl,2-hydroxyethyl, 1,3-dihydroxypropan-2-yl-, 2,3-dihydroxypropyl-,2-hydroxy-1,1-dimethyl-ethyl-, 2-hydroxy-2-methyl-propyl-,pyrrolidin-3-yl-, -3-pyrrolidine-1-carboxamide, hydrogen, benzyl,4-methoxybenzyl-, piperidin-4-yl-, piperidin-4-ylmethyl-, —CH₂CO₂CH₃,—CH₂CONH₂, 2-aminoethyl-, 1-hydroxypropan-2-yl-, —CH₂CH₂NHCO₂CH₃,—CH₂CH₂NHCONH₂; 3-trifluoromethylphenyl-, phenyl, 2-fluoroethyl-,3-hydroxypropyl, 2-methoxyethyl, 4-hydroxybutyl, 4-fluorobutyl, CONH₂,1-hydroxy-2-methylpropan-2-yl, oxetan-3-yl or —CH₂CO₂H,cyclopropylmethyl, or hydrogen;

In another particular embodiment of the invention, R³ is hydroxyethyl,particularly 2-hydroxyethyl, or hydrogen.

In another embodiment there is provided a compound of formula (I)

wherein

Y is C or N; X is CH or N; B is CH or N;

A is a ring;such that when X is CH and B is N, ring A is ring Ai or ring Aii;

when X is N and B is N, ring A is Aiii;

and when X is N and B is N, or X is N and B is CH, ring A is Ai;

R¹ is i:

R⁵ is 7-fluoro-quinolin-6-yl, quinolin-6-yl, 5,7-difluoroquinolin-6-yl,1-methyl-1H-indazol-5-yl, 6-fluoro-1-methyl-1H-indazol-5-yl,4,6-difluoro-1-methyl-1H-indazol-5-yl, 5-fluoroquinolin-6-yl,(4-methylpiperazin-1-yl)quinolin-6-yl or 6-quinolin-3-yl-ethanoneO-(2-hydroxy-ethyl)oximeR⁶ is hydrogen, deuterium, OH, methyl or halo;R⁷ is hydrogen, deuterium, halo, or (C₁-C₃)alkyl, wherein said(C₁-C₃)alkyl is optionally substituted by one or more substituentsindependently selected from OH and halo;or R⁶ and R⁷, together with the carbon to which they are attached formcyclopropyl;R² is hydrogen, NH₂, or (C₁-C₄)alkyl,and R³ is ethyl, methyl, 2-hydroxyethyl, 1,3-dihydroxypropan-2-yl-,2,3-dihydroxypropyl-, 2-hydroxy-1,1-dimethyl-ethyl-,2-hydroxy-2-methyl-propyl-, pyrrolidin-3-yl-,-3-pyrrolidine-1-carboxamide, hydrogen, benzyl, 4-methoxybenzyl-,piperidin-4-yl-, piperidin-4-ylmethyl-, —CH₂CO₂CH₃, —CH₂CONH₂,2-aminoethyl-, 1-hydroxypropan-2-yl-, —CH₂CH₂NHCO₂CH₃, —CH₂CH₂NHCONH₂;3-trifluoromethylphenyl-, phenyl, 2-fluoroethyl-, 3-hydroxypropyl,2-methoxyethyl, 4-hydroxybutyl, 4-fluorobutyl, CONH₂,1-hydroxy-2-methylpropan-2-yl, oxetan-3-yl, hydrogen, cyclopropylmethyl,or —CH₂CO₂H;or a pharmaceutically acceptable salt thereof.

In a further embodiment the invention provides a compound of formula (I)having a structure selected from (Ia), (Ib) or (Ic) above, wherein

R¹ is i:

R⁵ is quinolin-6-yl optionally substituted by one or two fluorosubstituents, the fluoro substituents being preferably in the 5 and/or 7positions;R⁶ is hydrogen;R⁷ is hydrogen or methyl;R² is methyl; andR³ is hydroxyethyl, more particularly 2-hydroxyethyl, or R³ is hydrogen;

Various embodiments of the invention are described herein. It will berecognized that features specified in each embodiment may be combinedwith other specified features to provide further embodiments.

In a particular embodiment, the invention provides one or more compoundsselected from the Example compounds disclosed herein, or apharmaceutically acceptable salt thereof.

FIG. 1 herein shows the X-ray diffractogram of Example 53S amorphousform. FIG. 2 shows the X-ray diffractogram of Example 53S crystallineform I. FIG. 3 shows the X-ray diffractogram of Example 53S crystallineform II.

As used herein, the term “isomers” refers to different compounds thathave the same molecular formula but differ in arrangement andconfiguration of the atoms. Also as used herein, the term “an opticalisomer” or “a stereoisomer” refers to any of the various stereo isomericconfigurations which may exist for a given compound of the presentinvention and includes geometric isomers. It is understood that asubstituent may be attached at a chiral center of a carbon atom.Therefore, the invention includes enantiomers, diastereomers orracemates of the compound. “Enantiomers” are a pair of stereoisomersthat are non-superimposable mirror images of each other. A 1:1 mixtureof a pair of enantiomers is a “racemic” mixture. The term is used todesignate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R-S system. When a compound is apure enantiomer the stereochemistry at each chiral carbon may bespecified by either R or S. Resolved compounds whose absoluteconfiguration is unknown can be designated (+) or (−) depending on thedirection (dextro- or levorotatory) which they rotate plane polarizedlight at the wavelength of the sodium D line. Certain of the compoundsdescribed herein contain one or more asymmetric centers or axes and maythus give rise to enantiomers, diastereomers, and other stereoisomericforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)-. The present invention is meant to include all such possibleisomers, including racemic mixtures, optically pure forms andintermediate mixtures. Optically active (R)- and (S)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. If the compound contains a double bond, thesubstituent may be E or Z configuration. If the compound contains adisubstituted cycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration. All tautomeric forms are also intended to beincluded.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration, such as forthe asymmetric carbon atom which may be present within the R¹ group (i)defined herein. In certain embodiments, each asymmetric atom has atleast 50% enantiomeric excess, at least 60% enantiomeric excess, atleast 70% enantiomeric excess, at least 80% enantiomeric excess, atleast 90% enantiomeric excess, at least 95% enantiomeric excess, or atleast 99% enantiomeric excess in the (R)- or (S)-configuration.Preferably for the asymmetric R¹ group (i) defined herein, the (S)enantiomer is in excess, in amounts as described above.

Substituents at atoms with unsaturated bonds may, if possible, bepresent in cis-(Z)- or trans-(E)-form. Preferably, the hydrazones of thepresent invention have the trans-(E)-form.

Accordingly, as used herein a compound of the present invention can bein the form of one of the possible isomers, rotamers, atropisomers,tautomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, fluorine, phosphorous, sulfur,chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P,³⁵S, ³⁶Cl, ¹²⁵I respectively. Various isotopically labeled compounds ofthe present invention, for example those into which radioactive isotopessuch as ³H, ¹³C, and ¹⁴C are incorporated. Such isotopically labelledcompounds are useful in metabolic studies (preferably with ¹⁴C),reaction kinetic studies (with, for example ²H or ³H), detection orimaging techniques [such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, an ¹⁸F or labeled compound may be particularlypreferred for PET or SPECT studies. Further, substitution with heavierisotopes such as deuterium (i.e., ²H) may afford certain therapeuticadvantages resulting from greater metabolic stability, for exampleincreased in vivo half-life or reduced dosage requirements. Isotopicallylabeled compounds of this invention and prodrugs thereof can generallybe prepared by carrying out the procedures disclosed in the schemes orin the examples and preparations described below by substituting areadily available isotopically labeled reagent for a non-isotopicallylabeled reagent.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the formula (I). The concentration of sucha heavier isotope, specifically deuterium, may be defined by theisotopic enrichment factor. The term “isotopic enrichment factor” asused herein means the ratio between the isotopic abundance and thenatural abundance of a specified isotope. If a substituent in a compoundof this invention is denoted deuterium, such compound has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation). Inthe compounds of this invention any atom not specifically designated asa particular isotope is meant to represent any stable isotope of thatatom. Unless otherwise stated, when a position is designatedspecifically as “H” or “hydrogen”, the position is understood to havehydrogen at its natural abundance isotopic composition. Accordingly, inthe compounds of this invention any atom specifically designated as adeuterium (D) is meant to represent deuterium, for example in the rangesgiven above.

Isotopically-labeled compounds of formula (I) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using an appropriate isotopically-labeled reagents in placeof the non-labeled reagent previously employed.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts that retain the biological effectiveness and properties of thecompounds of this invention and, which typically are not biologically orotherwise undesirable. The salt can be present alone or in mixture withfree compound of the formula (I). In many cases, the compounds of thepresent invention are capable of forming acid salts by virtue of thepresence of amino groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts. Inorganic acids from which salts can be derivedinclude, for example, hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, and the like. Organic acids fromwhich salts can be derived include, for example, acetic acid, propionicacid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid,sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases. Inorganic bases from which salts can bederived include, for example, ammonium salts and metals from columns Ito XII of the periodic table. In certain embodiments, the salts arederived from sodium, potassium, ammonium, calcium, magnesium, iron,silver, zinc, and copper; particularly suitable salts include ammonium,potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a parent compound, a basic or acidic moiety, byconventional chemical methods. Generally, such salts can be prepared byreacting free base forms of these compounds with a stoichiometric amountof the appropriate acid. Such reactions are typically carried out inwater or in an organic solvent, or in a mixture of the two. Generally,use of non-aqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile is desirable, where practicable. Lists ofadditional suitable salts can be found, e.g., in “Remington'sPharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton,Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties,Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany,2002). “Salts”, or “salts thereof” or “or a salt thereof”, can bepresent alone or in mixture with free compound of the formula (I).

For isolation or purification purposes it is also possible to usepharmaceutically unacceptable salts, for example picrates orperchlorates. For therapeutic use, only pharmaceutically acceptablesalts or free compounds are employed (where applicable in the form ofpharmaceutical preparations), and these are therefore preferred. In viewof the close relationship between the novel compounds in free form andthose in the form of their salts, including those salts that can be usedas intermediates, for example in the purification or identification ofthe novel compounds, any reference to the free compounds hereinbeforeand hereinafter is to be understood as referring also to thecorresponding salts, as appropriate and expedient.

The compounds of the invention may exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and one or morepharmaceutically acceptable solvent molecules, for example, ethanol. Theterm ‘hydrate’ is employed when said solvent is water. Pharmaceuticallyacceptable solvates include hydrates and other solvates wherein thesolvent of crystallization may be isotopically substituted, e.g. D₂O,d₆-acetone, d₆-DMSO. Any formula given herein is intended to representhydrates, solvates, and polymorphs of such compounds, and mixturesthereof.

Compounds of the invention, i.e. compounds of formula (I) that containgroups capable of acting as donors and/or acceptors for hydrogen bondsmay be capable of forming co-crystals with suitable co-crystal formers.These co-crystals may be prepared from compounds of formula (I) by knownco-crystal forming procedures. Such procedures include grinding,heating, co-subliming, co-melting, or contacting in solution compoundsof formula (I) with the co-crystal former under crystallizationconditions and isolating co-crystals thereby formed. Suitable co-crystalformers include those described in WO 2004/078163. Hence the inventionfurther provides co-crystals comprising a compound of formula (I).

The compounds of the invention therefore include compounds of formula I,polymorphs, and isomers thereof (including optical, geometric andtautomeric isomers) and isotopically-labelled compounds of formula I, asdefined herein. In preferred embodiments, which are preferredindependently, collectively or in any combination or sub-combination,the invention relates to a compound of the formula (I), in free baseform or in acid addition salt form, wherein the substituents are asdefined herein.

The compounds of the present invention may be administered as prodrugs.Thus certain derivatives of compounds of formula (I) which may havelittle or no pharmacological activity themselves can, when administeredinto or onto the body, be converted into compounds of formula (I) havingthe desired activity, for example, by hydrolytic cleavage. Suchderivatives are referred to as ‘prodrugs’. [Further information on theuse of prodrugs may be found in ‘Pro-drugs as Novel Delivery Systems,Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and‘Bioreversible Carriers in Drug Design’, Pergamon Press, 1987 (ed. E BRoche, American Pharmaceutical Association).]

Prodrugs can, for example, be produced by replacing appropriatefunctionalities present in the compounds of formula (I) with certainmoieties known to those skilled in the art as ‘pro-moieties’ asdescribed, for example, in “Design of Prodrugs” by H Bundgaard(Elsevier, 1985).

Some examples of such prodrugs include:

(i) where the compound of formula (I) contains a carboxylic acidfunctionality (—COOH), an ester thereof, for example, replacement of thehydrogen with (C₁-C₈)alkyl;(ii) where the compound of formula (I) contains an alcohol functionality(—OH), an ether thereof, for example, replacement of the hydrogen with(C₁-C₆)alkanoyloxymethyl; and(iii) where the compound of formula (I) contains a primary or secondaryamino functionality (—NH₂ or —NHR where R≠H), an amide thereof, forexample, replacement of one or both hydrogens with (C₁-C₁₀)alkanoyl.

Certain compounds of formula (I) may also themselves act as prodrugs ofother compounds of formula (I).

The invention further relates to a pharmaceutically acceptable prodrugof a compound of formula (I). The invention further relates to apharmaceutically acceptable metabolite of a compound of formula (I).

“C-Met tyrosine kinase mediated diseases” are especially such disordersthat respond in a beneficial way (e.g. amelioration of one or moresymptoms, delay of the onset of a disease, up to temporary or completecure from a disease) to the inhibition of a protein tyrosine kinase,especially inhibition of a c-Met kinase. These disorders includeproliferative diseases such as tumor diseases, in particular solidtumors and metastasis derived thereof, e.g. hereditary papillary renalcell carcinoma (PRCC), sporadic forms of PRCC, head and neck cancer,squamous cell carcinoma, gastric carcinoma, pancreatic carcinoma, lungcancer, bladder cancer, breast cancer, leiomyosarcoma, glioblastoma,melanoma, alveolar soft part sarcoma. These disorders further includeinflammatory conditions, such as inflammatory conditions due to aninfection.

“Combination” refers to either a fixed combination in one dosage unitform, or a kit of parts for the combined administration where a compoundof the formula (I) and a combination partner (e.g. an other drug asexplained below, also referred to as “therapeutic agent” or “co-agent”)may be administered independently at the same time or separately withintime intervals, especially where these time intervals allow that thecombination partners show a cooperative, e.g. synergistic effect. Theterms “co-administration” or “combined administration” or the like asutilized herein are meant to encompass administration of the selectedcombination partner to a single subject in need thereof (e.g. apatient), and are intended to include treatment regimens in which theagents are not necessarily administered by the same route ofadministration or at the same time. The term “pharmaceuticalcombination” as used herein means a product that results from the mixingor combining of more than one active ingredient and includes both fixedand non-fixed combinations of the active ingredients. The term “fixedcombination” means that the active ingredients, e.g. a compound offormula (I) and a combination partner, are both administered to apatient simultaneously in the form of a single entity or dosage. Theterm “non-fixed combination” means that the active ingredients, e.g. acompound of formula (I) and a combination partner, are both administeredto a patient as separate entities either simultaneously, concurrently orsequentially with no specific time limits, wherein such administrationprovides therapeutically effective levels of the two compounds in thebody of the patient. The latter also applies to cocktail therapy, e.g.the administration of three or more active ingredients.

The invention relates especially to a compound of the formula (I) asprovided in the Examples, as well as the methods of manufacturedescribed therein.

The compounds of formula (I) have valuable pharmacological properties,as described hereinbefore and hereinafter.

In another embodiment of the invention, there is provided a method fortreating a c-Met related disorder or condition. The disorder orcondition to be treated is preferably a proliferative disease such as acancer or an inflammatory condition. Compounds of formula (I) arefurther useful for treating diseases associated with a c-Met-relatedcondition.

A: Proliferative diseases: Compounds of formula (I) are particularuseful for the treatment of one or more of the following proliferativediseases:

Compounds of formula (I) are useful in the treatment of cancer whereinthe cancer is selected from the group consisting of brain cancer,stomach cancer, genital cancer, urinary cancer, prostate cancer, bladdercancer (superficial and muscle invasive), breast cancer, cervicalcancer, colon cancer, colorectal cancer, glioma (including glioblastoma,anaplastic astrocytoma, oligoastrocytoma, oligodendroglioma), esophagealcancer, gastric cancer, gastrointestinal cancer, liver cancer,hepatocellular carcinoma (HCC) including childhood HCC, head and neckcancer (including head and neck squamous-cell carcinoma, nasopharyngealcarcinoma), Hurthle cell carcinoma, epithelial cancer, skin cancer,melanoma (including malignant melanoma), mesothelioma, lymphoma, myeloma(including multiple myeloma), leukemias, lung cancer (includingnon-small cell lung cancer (including all histological subtypes:adenocarcinoma, squamous cell carcinoma, bronchoalveolar carcinoma,large-cell carcinoma, and adenosquamous mixed type), small-cell lungcancer), ovarian cancer, pancreatic cancer, prostate cancer, kidneycancer (including but not limited to papillary renal cell carcinoma),intestine cancer, renal cell cancer (including hereditary and sporadicpapillary renal cell cancer, Type I and Type II, and clear cell renalcell cancer); sarcomas, in particular osteosarcomas, clear cellsarcomas, and soft tissue sarcomas (including alveolar and embryonalrhabdomyosarcomas, alveolar soft part sarcomas); and thyroid carcinoma(papillary and other subtypes).

Compounds of formula (I) are useful in the treatment of cancer whereinthe cancer is stomach, colon, liver, genital, urinary, melanoma, orprostate. In a particular embodiment, the cancer is liver or esophageal.

Compounds of formula (I) are useful in the treatment of colon cancer,including metastases, e.g. in the liver, and of non-small-cell lungcarcinoma.

Compounds of formula (I) may also be used in the treatment of hereditarypapillary renal carcinoma (Schmidt, L. et al. Nat. Genet. 16, 68-73,1997) and other proliferative diseases in which c-Met is overexpressedor constitutively activated by mutations (Jeffers and Vande Woude.Oncogene 18, 5120-5125, 1999; and reference cited therein) orchromosomal rearrangements (e.g. TPR-MET; Cooper et al. Nature 311,29-33, 1984; Park. et al. Cell 45, 895-904, 1986).

Compounds of formula (I) are further useful in the treatment ofadditional cancers and conditions as provided herein or known in theart.

B: Inflammatory conditions: Compounds of formula (I) are particularsuitable for the treatment of one or more inflammatory conditions.

In a further embodiment, the inflammatory condition is due to aninfection. In one embodiment, the method of treatment would be to blockpathogen infection. In a particular embodiment, the infection is abacterial infection, e.g., a Listeria infection. See, e.g., Shen et al.Cell 103: 501-10, (2000) whereby a bacterial surface protein activatesc-Met kinase through binding to the extracellular domain of thereceptor, thereby mimicking the effect of the cognate ligand HGF/SF.

Compounds of formula (I) are further useful in the treatment ofadditional inflammatory disorders and conditions as provided herein orknown in the art.

C: Combination therapy: In certain embodiments, any of the above methodsinvolve further administering a chemotherapeutic agent.

In a related embodiment, the chemotherapeutic agent is an anti-canceragent. Specific combinations are provided throughout the application.

In a further related embodiment, any of the above methods involvefurther administering a pathway specific inhibitor. The pathway specificinhibitor may be a chemotherapeutic agent or may be a biologic agent,e.g., antibodies. Pathway specific inhibitors include, but are notlimited to, inhibitors of EGFR, Her-2, Her-3, VEGFR, Ron, IGF-IR, PI-3K,mTOR, and Raf.

In a further related embodiment to several of the above methods,following administering to the subject or contacting the cell, thesemethods can further involve observing amelioration or retardation ofdevelopment or metastasis of the cancer.

Thus, in one embodiment, the invention relates to a method of treating ac-Met related disorder or condition which involves administering to asubject in need thereof an effective amount of a compound of formula(I).

In a further embodiment, the invention relates to a compound of formula(I) or a pharmaceutically acceptable salt thereof, for use as amedicament, in particular for the treatment of one or more C-Mettyrosine kinase mediated diseases.

In a further embodiment, the invention relates to the use of a compoundof formula (I) or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment of one or more C-Mettyrosine kinase mediated diseases.

In a further embodiment, the invention relates to a method for thetreatment of a disease or disorder which responds to an inhibition ofC-Met tyrosine kinase, which comprises administering a compound offormula (I) or a pharmaceutically acceptable salt thereof, especially ina quantity effective against said disease, to a warm-blooded animalrequiring such treatment.

In a further embodiment, the invention relates to a pharmaceuticalcomposition comprising a compound of formula (I) as active ingredient inassociation with at least one pharmaceutical carrier or diluent.

In a further embodiment, the invention relates to a pharmaceuticalcomposition comprising: (a) an effective amount of compound of formula(I) and pharmaceutically acceptable salts, pharmaceutically acceptableprodrugs, and/or pharmaceutically active metabolites thereof; and (b)one or more pharmaceutically acceptable excipients and/or diluents.

In a further embodiment, the invention relates to a pharmaceuticalcomposition for treatment of a disease, e.g. of solid or liquid tumoursin warm-blooded animals, including humans, comprising a dose effectivein the treatment of said disease of a compound of the formula (I) asdescribed above or a pharmaceutically acceptable salt of such a compoundtogether with a pharmaceutically acceptable carrier (=carrier material).

In another embodiment of the invention, there is provided apharmaceutical preparation (composition), comprising a compound offormula (I) as defined herein, or a pharmaceutically acceptable salt ofsuch a compound, or a hydrate or solvate thereof, and at least onepharmaceutically acceptable carrier and/or diluents and optionally oneor more further therapeutic agents.

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drugs, drug stabilizers, binders, excipients,disintegration agents, lubricants, sweetening agents, flavoring agents,dyes, and the like and combinations thereof, as would be known to thoseskilled in the art (see, for example, Remington's PharmaceuticalSciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Exceptinsofar as any conventional carrier is incompatible with the activeingredient, its use in the therapeutic or pharmaceutical compositions iscontemplated.

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response of asubject, for example, reduction or inhibition of an enzyme or a proteinactivity, or ameliorate symptoms, alleviate conditions, slow or delaydisease progression, or prevent a disease, etc. In one non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a subject, is effective to (1) at least partially alleviating,inhibiting, preventing and/or ameliorating a condition, or a disorder ora disease (i) mediated by c-Met or (ii) associated with c-Met activity,or (iii) characterized by activity (normal or abnormal) of c-Met; or (2)reducing or inhibiting the activity of c-Met; or (3) reducing orinhibiting the expression of c-Met. In another non-limiting embodiment,the term “a therapeutically effective amount” refers to the amount ofthe compound of the present invention that, when administered to a cell,or a tissue, or a non-cellular biological material, or a medium, iseffective to at least partially reducing or inhibiting the activity ofc-Met; or at least partially reducing or inhibiting the expression ofc-Met.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A subject also refers to for example, primates(e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats,mice, fish, birds and the like. In certain embodiments, the subject is aprimate. In yet other embodiments, the subject is a human.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treat”, “treating” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treat”, “treating” or “treatment” refers tomodulating the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both. In yet anotherembodiment, “treat”, “treating” or “treatment” refers to preventing ordelaying the onset or development or progression of the disease ordisorder.

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention and apharmaceutically acceptable carrier. The pharmaceutical composition canbe formulated for particular routes of administration such as oraladministration, parenteral administration, and rectal administration,etc. In addition, the pharmaceutical compositions of the presentinvention can be made up in a solid form (including without limitationcapsules, tablets, pills, granules, powders or suppositories), or in aliquid form (including without limitation solutions, suspensions oremulsions). The pharmaceutical compositions can be subjected toconventional pharmaceutical operations such as sterilization and/or cancontain conventional inert diluents, lubricating agents, or bufferingagents, as well as adjuvants, such as preservatives, stabilizers,wetting agents, emulsifers and buffers, etc.

Typically, the pharmaceutical compositions are tablets or gelatincapsules comprising the active ingredient together with

-   -   a) diluents, e.g., lactose, dextrose, sucrose, mannitol,        sorbitol, cellulose and/or glycine;    -   b) lubricants, e.g., silica, talcum, stearic acid, its magnesium        or calcium salt and/or polyethyleneglycol; for tablets also    -   c) binders, e.g., magnesium aluminum silicate, starch paste,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and/or polyvinylpyrrolidone; if desired    -   d) disintegrants, e.g., starches, agar, alginic acid or its        sodium salt, or effervescent mixtures; and/or    -   e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets may contain the active ingredient in admixturewith nontoxic pharmaceutically acceptable excipients which are suitablefor the manufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, or contain about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with a suitable carrier. Carrierssuitable for transdermal delivery include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Forexample, transdermal devices are in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundof the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. They arethus particularly suited for use in topical, including cosmetic,formulations well-known in the art. Such may contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

As used herein a topical application may also pertain to an inhalationor to an intranasal application. They may be conveniently delivered inthe form of a dry powder (either alone, as a mixture, for example a dryblend with lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurised container, pump, spray, atomizer ornebuliser, with or without the use of a suitable propellant.

The invention relates also to a pharmaceutical composition comprising aneffective amount, especially an amount effective in the treatment of oneof the above-mentioned diseases, disorders or conditions, of a compoundof formula (I) or a pharmaceutically acceptable salt thereof, togetherwith one or more pharmaceutically acceptable carriers that are suitablefor topical, enteral, for example oral or rectal, or parenteraladministration and that may be inorganic or organic, solid or liquid.

The dosage of the active ingredient to be applied to a warm-bloodedanimal depends upon a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal andhepatic function of the patient; and the particular compound employed. Aphysician, clinician or veterinarian of ordinary skill can readilydetermine and prescribe the effective amount of the drug required toprevent, counter or arrest the progress of the condition. Optimalprecision in achieving concentration of drug within the range thatyields efficacy without toxicity requires a regimen based on thekinetics of the drug's availability to target sites. This involves aconsideration of the distribution, equilibrium, and elimination of adrug. The dose of a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof to be administered to warm-blooded animals, forexample humans of approximately 70 kg body weight, is preferably fromapproximately 3 mg to approximately 5 g, more preferably fromapproximately 10 mg to approximately 1.5 g per person per day, dividedpreferably into 1 to 3 single doses which may, for example, be of thesame size. Usually, children receive half of the adult dose.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredient(s) for asubject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.The therapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of thepresent invention can be applied in vitro in the form of solutions,e.g., aqueous solutions, and in vivo either enterally, parenterally,advantageously intravenously, e.g., as a suspension or in aqueoussolution. The dosage in vitro may range between about 10⁻³ molar and10⁻⁹ molar concentrations. A therapeutically effective amount in vivomay range depending on the route of administration, between about0.1-500 mg/kg, or between about 1-100 mg/kg.

In another embodiment of the invention, there is provided a combinationof a compound of formula (I) with one or more other therapeuticallyactive agents. Thus, a compound of formula (I) can be administered aloneor in combination with one or more other therapeutic agents, possiblecombination therapy taking the form of fixed combinations or theadministration of a compound of the invention and one or more othertherapeutic agents being staggered or given independently of oneanother, or the combined administration of fixed combinations and one ormore other therapeutic agents.

A compound of formula (I) can besides or in addition be administeredespecially for tumor therapy in combination with chemotherapy,radiotherapy, immunotherapy, surgical intervention, or a combination ofthese. Long-term therapy is equally possible as is adjuvant therapy inthe context of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumor regression, or even chemopreventive therapy, for example inpatients at risk.

Thus, a compound of the formula (I) may be used in combination withother antiproliferative compounds. Such antiproliferative compoundsinclude, but are not limited to aromatase inhibitors; antiestrogens;topoisomerase I inhibitors; topoisomerase II inhibitors; microtubuleactive compounds; alkylating compounds; histone deacetylase inhibitors;compounds which induce cell differentiation processes; cyclooxygenaseinhibitors; MMP inhibitors; mTOR inhibitors; antineoplasticantimetabolites; platin compounds; compounds targeting/decreasing aprotein or lipid kinase activity; anti-angiogenic compounds; compoundswhich target, decrease or inhibit the activity of a protein or lipidphosphatase; gonadorelin agonists; anti-androgens; methionineaminopeptidase inhibitors; bisphosphonates; biological responsemodifiers; antiproliferative antibodies; heparanase inhibitors;inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasomeinhibitors; compounds used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of Flt-3; Hsp90inhibitors; kinesin spindle protein inhibitors; MEK inhibitors;leucovorin; EDG binders; antileukemia compounds; ribonucleotidereductase inhibitors; S-adenosylmethionine decarboxylase inhibitors;angiostatic steroids; corticosteroids; other chemotherapeutic compounds(as defined below); photosensitizing compounds.

Further, alternatively or in addition they may be used in combinationwith other tumor treatment approaches, including surgery, ionizingradiation, photodynamic therapy, implants, e.g. with corticosteroids,hormones, or they may be used as radiosensitizers.

The term “aromatase inhibitor” as used herein relates to a compoundwhich inhibits the estrogen production, i.e. the conversion of thesubstrates androstenedione and testosterone to estrone and estradiol,respectively. The term includes, but is not limited to steroids,especially atamestane, exemestane and formestane and, in particular,non-steroids, especially aminoglutethimide, roglethimide,pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole,fadrozole, anastrozole and letrozole. Exemestane can be administered,e.g., in the form as it is marketed, e.g. under the trademark AROMASIN.Formestane can be administered, e.g., in the form as it is marketed,e.g. under the trademark LENTARON. Fadrozole can be administered, e.g.,in the form as it is marketed, e.g. under the trademark AFEMA.Anastrozole can be administered, e.g., in the form as it is marketed,e.g. under the trademark ARIMIDEX. Letrozole can be administered, e.g.,in the form as it is marketed, e.g. under the trademark FEMARA or FEMAR.Aminoglutethimide can be administered, e.g., in the form as it ismarketed, e.g. under the trademark ORIMETEN. A combination of theinvention comprising a chemotherapeutic agent which is an aromataseinhibitor is particularly useful for the treatment of hormone receptorpositive tumors, e.g. breast tumors.

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen can be administered, e.g., inthe form as it is marketed, e.g. under the trademark NOLVADEX.Raloxifene hydrochloride can be administered, e.g., in the form as it ismarketed, e.g. under the trademark EVISTA. Fulvestrant can be formulatedas disclosed in U.S. Pat. No. 4,659,516 or it can be administered, e.g.,in the form as it is marketed, e.g. under the trademark FASLODEX. Acombination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, e.g. breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (CASODEX), which canbe formulated, e.g. as disclosed in U.S. Pat. No. 4,636,505. The term“gonadorelin agonist” as used herein includes, but is not limited toabarelix, goserelin and goserelin acetate. Goserelin is disclosed inU.S. Pat. No. 4,100,274 and can be administered, e.g., in the form as itis marketed, e.g. under the trademark ZOLADEX. Abarelix can beformulated, e.g. as disclosed in U.S. Pat. No. 5,843,901.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148 (compound A1 in WO99/17804). Irinotecan can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark CAMPTOSAR. Topotecan can be administered, e.g., in the form asit is marketed, e.g. under the trademark HYCAMTIN.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, e.g. CAELYX), daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide can be administered, e.g. in the form as it is marketed, e.g.under the trademark ETOPOPHOS. Teniposide can be administered, e.g. inthe form as it is marketed, e.g. under the trademark VM 26-BRISTOL.Doxorubicin can be administered, e.g. in the form as it is marketed,e.g. under the trademark ADRIBLASTIN or ADRIAMYCIN. Epirubicin can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark FARMORUBICIN. Idarubicin can be administered, e.g. in the formas it is marketed, e.g. under the trademark ZAVEDOS. Mitoxantrone can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark NOVANTRON.

The term “microtubule active compound” relates to microtubulestabilizing, microtubule destabilizing compounds and microtublinpolymerization inhibitors including, but not limited to taxanes, e.g.paclitaxel and docetaxel, vinca alkaloids, e.g., vinblastine, especiallyvinblastine sulfate, vincristine especially vincristine sulfate, andvinorelbine, discodermolides, cochicine and epothilones and derivativesthereof, e.g. epothilone B or D or derivatives thereof. Paclitaxel maybe administered e.g. in the form as it is marketed, e.g. TAXOL.Docetaxel can be administered, e.g., in the form as it is marketed, e.g.under the trademark TAXOTERE. Vinblastine sulfate can be administered,e.g., in the form as it is marketed, e.g. under the trademark VINBLASTINR.P. Vincristine sulfate can be administered, e.g., in the form as it ismarketed, e.g. under the trademark FARMISTIN. Discodermolide can beobtained, e.g., as disclosed in U.S. Pat. No. 5,010,099. Also includedare Epothilone derivatives which are disclosed in WO 98/10121, U.S. Pat.No. 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO00/31247. Especially preferred are Epothilone A and/or B.

The term “alkylating compound” as used herein includes, but is notlimited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNUor Gliadel). Cyclophosphamide can be administered, e.g., in the form asit is marketed, e.g. under the trademark CYCLOSTIN. Ifosfamide can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark HOLOXAN.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes compounds disclosed in WO02/22577, especiallyN-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamideand pharmaceutically acceptable salts thereof. It further especiallyincludes Suberoylanilide hydroxamic acid (SAHA). Compounds which target,decrease or inhibit activity of histone deacetylase (HDAC) inhibitorssuch as sodium butyrate and suberoylanilide hydroxamic acid (SAHA)inhibit the activity of the enzymes known as histone deacetylases.Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228),Trichostatin A and compounds disclosed in U.S. Pat. No. 6,552,065, inparticular,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, especially the lactatesalt.

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-Fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabinecan be administered, e.g., in the form as it is marketed, e.g. under thetrademark XELODA. Gemcitabine can be administered, e.g., in the form asit is marketed, e.g. under the trademark GEMZAR.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark CARBOPLAT. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark ELOXATIN.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity”; or a “protein or lipid phosphatase activity”; or “furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, c-Met tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, e.g.,

a) compounds targeting, decreasing or inhibiting the activity of theplatelet-derived growth factor-receptors (PDGFR), such as compoundswhich target, decrease or inhibit the activity of PDGFR, especiallycompounds which inhibit the PDGF receptor, e.g. aN-phenyl-2-pyrimidine-amine derivative, e.g. imatinib, SU101, SU6668 andGFB-111;b) compounds targeting, decreasing or inhibiting the activity of thefibroblast growth factor-receptors (FGFR);c) compounds targeting, decreasing or inhibiting the activity of theinsulin-like growth factor receptor I (IGF-IR), such as compounds whichtarget, decrease or inhibit the activity of IGF-IR, especially compoundswhich inhibit the kinase activity of IGF-1 receptor, such as thosecompounds disclosed in WO 02/092599, or antibodies that target theextracellular domain of IGF-I receptor or its growth factors;d) compounds targeting, decreasing or inhibiting the activity of the Trkreceptor tyrosine kinase family, or ephrin kinase family inhibitors;e) compounds targeting, decreasing or inhibiting the activity of the Axlreceptor tyrosine kinase family;f) compounds targeting, decreasing or inhibiting the activity of the Retreceptor tyrosine kinase;g) compounds targeting, decreasing or inhibiting the activity of theKit/SCFR receptor tyrosine kinase, e.g. imatinib;h) compounds targeting, decreasing or inhibiting the activity of theC-kit receptor tyrosine kinases—(part of the PDGFR family), such ascompounds which target, decrease or inhibit the activity of the c-Kitreceptor tyrosine kinase family, especially compounds which inhibit thec-Kit receptor, e.g. imatinib;i) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase)and mutants, such as compounds which target decrease or inhibit theactivity of c-Abl family members and their gene fusion products, e.g. aN-phenyl-2-pyrimidine-amine derivative, e.g. imatinib or nilotinib(AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825)j) compounds targeting, decreasing or inhibiting the activity of membersof the protein kinase C (PKC) and Raf family of serine/threoninekinases, members of the MEK, SRC, JAK, FAK, PDK1, PKB/Akt, and Ras/MAPKfamily members, and/or members of the cyclin-dependent kinase family(CDK) and are especially those staurosporine derivatives disclosed inU.S. Pat. No. 5,093,330, e.g. midostaurin; examples of further compoundsinclude e.g. UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine;Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521;LY333531/LY379196; isochinoline compounds such as those disclosed in WO00/09495; FTIs; PD184352 or QAN697 (a PI3K inhibitor) or AT7519 (CDKinhibitor);k) compounds targeting, decreasing or inhibiting the activity ofprotein-tyrosine kinase inhibitors, such as compounds which target,decrease or inhibit the activity of protein-tyrosine kinase inhibitorsinclude imatinib mesylate (GLEEVEC) or tyrphostin. A tyrphostin ispreferably a low molecular weight (Mr<1500) compound, or apharmaceutically acceptable salt thereof, especially a compound selectedfrom the benzylidenemalonitrile class or the S-arylbenzenemalonirile orbisubstrate quinoline class of compounds, more especially any compoundselected from the group consisting of Tyrphostin A23/RG-50810; AG 99;Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; TyrphostinB44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494;Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin);l) compounds targeting, decreasing or inhibiting the activity of theepidermal growth factor family of receptor tyrosine kinases (EGFR,ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such ascompounds which target, decrease or inhibit the activity of theepidermal growth factor receptor family are especially compounds,proteins or antibodies which inhibit members of the EGF receptortyrosine kinase family, e.g. EGF receptor, ErbB2, ErbB3 and ErbB4 orbind to EGF or EGF related ligands, and are in particular thosecompounds, proteins or monoclonal antibodies generically andspecifically disclosed in WO 97/02266, e.g. the compound of ex. 39, orin EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP0 837 063, U.S. Pat. No. 5,747,498, WO 98/10767, WO 97/30034, WO97/49688, WO 97/38983 and, especially, WO 96/30347 (e.g. compound knownas CP 358774), WO 96/33980 (e.g. compound ZD 1839) and WO 95/03283 (e.g.compound ZM105180); e.g. trastuzumab (Herceptin™), cetuximab (Erbitux™),Iressa, Tarceva, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5,E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidinederivatives which are disclosed in WO 03/013541; andm) compounds targeting, decreasing or inhibiting the activity of thec-Met receptor, such as compounds which target, decrease or inhibit theactivity of c-Met, especially compounds which inhibit the kinaseactivity of c-Met receptor, or antibodies that target the extracellulardomain of c-Met or bind to HGF;n) compounds targeting, decreasing or inhibiting the activity of the Ronreceptor tyrosine kinase.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (THALOMID) and TNP-470.

The term “Compounds which target, decrease or inhibit the activity of aprotein or lipid phosphatase” includes, but is not limited to inhibitorsof phosphatase 1, phosphatase 2A, or CDC25, e.g. okadaic acid or aderivative thereof.

The term “Compounds which induce cell differentiation processes”includes, but is not limited to e.g. retinoic acid, α- γ- orδ-tocopherol or α- γ- or δ-tocotrienol.

The term “cyclooxygenase inhibitor” as used herein includes, but is notlimited to, e.g. Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, e.g.5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. “Etridonic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark DIDRONEL. “Clodronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark BONEFOS. “Tiludronicacid” can be administered, e.g., in the form as it is marketed, e.g.under the trademark SKELID. “Pamidronic acid” can be administered, e.g.in the form as it is marketed, e.g. under the trademark AREDIA™.“Alendronic acid” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark FOSAMAX. “Ibandronic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark BONDRANAT. “Risedronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark ACTONEL. “Zoledronicacid” can be administered, e.g. in the form as it is marketed, e.g.under the trademark ZOMETA. The term “mTOR inhibitors” relates tocompounds which inhibit the mammalian target of rapamycin (mTOR) andwhich possess antiproliferative activity such as sirolimus (Rapamune®),everolimus (Certican™), CCI-779 and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88.

The term “biological response modifier” as used herein refers to alymphokine or interferons, e.g. interferon γ.

The term “inhibitor of Ras oncogenic isoforms”, e.g. H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras e.g. a “farnesyl transferaseinhibitor” e.g. L-744832, DK8G557 or R115777 (Zarnestra).

The term “telomerase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of telomerase. Compounds whichtarget, decrease or inhibit the activity of telomerase are especiallycompounds which inhibit the telomerase receptor, e.g. telomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase are e.g. bengamide or a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasome includee.g. Bortezomid (Velcade™) and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors e.g. compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-b-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitorse.g. compounds which target, decrease or inhibit anaplastic lymphomakinase.

The term “Compounds which target, decrease or inhibit the activity ofFMS-like tyrosine kinase receptors (Flt-3R)” are especially compounds,proteins or antibodies which inhibit members of the Flt-3R receptorkinase family, e.g. PKC412, midostaurin, a staurosporine derivative,SU11248 and MLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90 e.g., 17-allylamino,17-demethoxygeldanamycin(17AAG, 17-DMAG), a geldanamycin derivative; other geldanamycin relatedcompounds; radicicol and HDAC inhibitors; IPI-504, CNF1010, CNF2024,CNF1010 from Conforma Therapeutics; temozolomide (TEMODAL®), AUY922 fromNovartis.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux,bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and2C4 Antibody. By antibodies is meant e.g. intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least 2intact antibodies, and antibodies fragments so long as they exhibit thedesired biological activity.

The term “antileukemic compounds” includes, for example, Ara-C, apyrimidine analog, which is the 2′-alpha-hydroxy ribose (arabinoside)derivative of deoxycytidine. Also included is the purine analog ofhypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. For thetreatment of acute myeloid leukemia (AML), compounds of formula (I) canbe used in combination with standard leukemia therapies, especially incombination with therapies used for the treatment of AML. In particular,compounds of formula (I) can be administered in combination with, e.g.,farnesyl transferase inhibitors and/or other drugs useful for thetreatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16,Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.

“Somatostatin receptor antagonists” as used herein refers to compoundswhich target, treat or inhibit the somatostatin receptor such asoctreotide, and SOM230.

“Tumor cell damaging approaches” refer to approaches such as ionizingradiation. The term “ionizing radiation” referred to above andhereinafter means ionizing radiation that occurs as eitherelectromagnetic rays (such as X-rays and gamma rays) or particles (suchas alpha and beta particles). Ionizing radiation is provided in, but notlimited to, radiation therapy and is known in the art. See Hellman,Principles of Radiation Therapy, Cancer, in Principles and Practice ofOncology, Devita et al., Eds., 4^(th) Edition, Vol. 1, pp. 248-275(1993).

The term “EDG binders” as used herein refers a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFTY720.

The term “kinesin spindle protein inhibitors” is known in the field andincludes SB715992 or SB743921 from GlaxoSmithKline,pentamidine/chlorpromazine from CombinatoRx;

The term “MEK inhibitors” is known in the field and includes ARRY142886from Array PioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer,leucovorin.

The term “ribonucleotide reductase inhibitors” includes, but is notlimited to pyrimidine or purine nucleoside analogs including, but notlimited to, fludarabine and/or cytosine arabinoside (ara-C),6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especiallyin combination with ara-C against ALL) and/or pentostatin.Ribonucleotide reductase inhibitors are especially hydroxyurea or2-hydroxy-1H-isoindole-1,3-dione derivatives, such as PL-1, PL-2, PL-3,PL-4, PL-5, PL-6, PL-7 or PL-8 mentioned in Nandy et al., ActaOncologica, Vol. 33, No. 8, pp. 953-961 (1994).

The term “S-adenosylmethionine decarboxylase inhibitors” as used hereinincludes, but is not limited to the compounds disclosed in U.S. Pat. No.5,461,076.

Also included are in particular those compounds, proteins or monoclonalantibodies of VEGF/VEGFR disclosed in WO 98/35958, e.g.1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof, e.g. the succinate, or in WO 00/09495, WO00/27820, WO 00/59509, WO 98/11223, WO 00/27819 and EP 0 769 947; thoseas described by Prewett et al, Cancer Res, Vol. 59, pp. 5209-5218(1999); Yuan et al., Proc Natl Acad Sci USA, Vol. 93, pp. 14765-14770(1996); Zhu et al., Cancer Res, Vol. 58, pp. 3209-3214 (1998); andMordenti et al., Toxicol Pathol, Vol. 27, No. 1, pp. 14-21 (1999); in WO00/37502 and WO 94/10202; ANGIOSTATIN, described by O'Reilly et al.,Cell, Vol. 79, pp. 315-328 (1994); ENDOSTATIN, described by O'Reilly etal., Cell, Vol. 88, pp. 277-285 (1997); anthranilic acid amides; ZD4190;ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies oranti-VEGF receptor antibodies, e.g. rhuMAb and RHUFab, VEGF aptamer e.g.Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgG1 antibody,Angiozyme (RPI 4610) and Bevacizumab (Avastin™).

“Photodynamic therapy” as used herein refers to therapy which usescertain chemicals known as photosensitizing compounds to treat orprevent cancers. Examples of photodynamic therapy includes treatmentwith compounds, such as e.g. VISUDYNE and porfimer sodium.

“Angiostatic steroids” as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone,hydrocortisone, 11-α-epihydrocotisol, cortexolone,17α-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

“Corticosteroids” as used herein includes, but is not limited tocompounds, such as e.g. fluocinolone, dexamethasone; in particular inthe form of implants.

“Other chemotherapeutic compounds” include, but are not limited to,plant alkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

A compound of formula (I) may also be used in combination with one ormore further drug substances selected from the group ofanti-inflammatory drug substances; antihistamine drug substances;bronchodilatatory drug substances, NSAID; antagonists of chemokinereceptors.

The compounds of the invention are also useful as co-therapeuticcompounds for use in combination with such further drug substances,particularly in the treatment of inflammatory diseases such as thosementioned hereinbefore, for example as potentiators of therapeuticactivity of such drugs or as a means of reducing required dosaging orpotential side effects of such drugs. A compound of the invention may bemixed with such other drug substance in a fixed pharmaceuticalcomposition or it may be administered separately (i.e. before,simultaneously with or after the other drug substance). Accordingly, theinvention includes a combination of a compound of formula (I) with oneor more further drug substance selected from the group ofanti-inflammatory drug substances; antihistamine drug substances;bronchodilatatory drug substances, NSAID antagonists of chemokinereceptors; said compound of the formula (I) and said drug substancebeing in the same or different pharmaceutical composition.

Suitable anti-inflammatory drugs include steroids, in particularglucocorticosteroids such as budesonide, beclamethasone dipropionate,fluticasone propionate, ciclesonide or mometasone furoate, or steroidsdescribed in WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679(especially those of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60,67, 72, 73, 90, 99 and 101), WO 03/035668, WO 03/048181, WO 03/062259,WO 03/064445, WO 03/072592, non-steroidal glucocorticoid receptoragonists such as those described in WO 00/00531, WO 02/10143, WO03/082280, WO 03/082787, WO 03/104195, WO 04/005229; LTB4 antagonistssuch LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB209247 and those described in U.S. Pat. No. 5,451,700; LTD4 antagonistssuch as montelukast and zafirlukast; PDE4 inhibitors such cilomilast(Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A (Napp),BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (AlmirallProdesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281 (Asta Medica),CDC-801 (Celgene), SelCID(TM) CC-10004 (Celgene), VM554/UM565(Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo), and thosedisclosed in WO 92/19594, WO 93/19749, WO 93/19750, WO 93/19751, WO98/18796, WO 99/16766, WO 01/13953, WO 03/104204, WO 03/104205, WO03/39544, WO 04/000814, WO 04/000839, WO 04/005258, WO 04/018450, WO04/018451, WO 04/018457, WO 04/018465, WO 04/018431, WO 04/018449, WO04/018450, WO 04/018451, WO 04/018457, WO 04/018465, WO 04/019944, WO04/019945, WO 04/045607 and WO 04/037805; Ata agonists such as thosedisclosed in EP 409595A2, EP 1052264, EP 1241176, WO 94/17090, WO96/02543, WO 96/02553, WO 98/28319, WO 99/24449, WO 99/24450, WO99/24451, WO 99/38877, WO 99/41267, WO 99/67263, WO 99/67264, WO99/67265, WO 99/67266, WO 00/23457, WO 00/77018, WO 00/78774, WO01/23399, WO 01/27130, WO 01/27131, WO 01/60835, WO 01/94368, WO02/00676, WO 02/22630, WO 02/96462, WO 03/086408, WO 04/039762, WO04/039766, WO 04/045618 and WO 04/046083; A2b antagonists such as thosedescribed in WO 02/42298; and beta-2 adrenoceptor agonists such asalbuterol (salbutamol), metaproterenol, terbutaline, salmeterolfenoterol, procaterol, and especially, formoterol and pharmaceuticallyacceptable salts thereof, and compounds (in free or salt or solvateform) of formula I of WO 0075114, which document is incorporated hereinby reference, preferably compounds of the Examples thereof, especially acompound of formula

and pharmaceutically acceptable salts thereof, as well as compounds (infree or salt or solvate form) of formula I of WO 04/16601, and alsocompounds of WO 04/033412.

Suitable bronchodilatory drugs include anticholinergic or antimuscariniccompounds, in particular ipratropium bromide, oxitropium bromide,tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but alsothose described in WO 01/04118, WO 02/51841, WO 02/53564, WO 03/00840,WO 03/87094, WO 04/05285, WO 02/00652, WO 03/53966, EP 424021, U.S. Pat.No. 5,171,744, U.S. Pat. No. 3,714,357, WO 03/33495 and WO 04/018422.

Suitable chemokine receptors include, e.g. CCR-1, CCR-2, CCR-3, CCR-4,CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4,CXCR5, particularly CCR-5 antagonists such as Schering-Ploughantagonists SC-351125, SCH-55700 and SCH-D, Takeda antagonists such asN-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminiumchloride (TAK-770), and CCR-5 antagonists described in U.S. Pat. No.6,166,037 (particularly claims 18 and 19), WO 00/66558 (particularlyclaim 8), WO 00/66559 (particularly claim 9), WO 04/018425 and WO04/026873.

Suitable antihistamine drug substances include cetirizine hydrochloride,acetaminophen, clemastine fumarate, promethazine, loratidine,desloratidine, diphenhydramine and fexofenadine hydrochloride,activastine, astemizole, azelastine, ebastine, epinastine, mizolastineand tefenadine as well as those disclosed in WO 03/099807, WO 04/026841and JP 2004107299.

Therapeutic agents for possible combination are especially one or moreantiproliferative, cytostatic or cytotoxic compounds, for example one orseveral agents selected from the group which includes, but is notlimited to, an inhibitor of polyamine biosynthesis, an inhibitor of aprotein kinase, especially of a serine/threonine protein kinase, such asprotein kinase C, or of a tyrosine protein kinase, such as the EGFreceptor tyrosine kinase, e.g. Iressa®, the VEGF receptor tyrosinekinase, e.g. PTK787 or Avastin®, an antibody against the ligand VEGF, orthe PDGF receptor tyrosine kinase, e.g. STI571 (Glivec®), PI3K (such asBEZ235 from Novartis) and mToR inhibitors, such as rapamycin, RAD001, acytokine, a negative growth regulator, such as TGF-β or IFN-β, anaromatase inhibitor, e.g. letrozole (Femara®) or anastrozole, aninhibitor of the interaction of an SH2 domain with a phosphorylatedprotein, antiestrogens, topoisomerase I inhibitors, such as irinotecan,topoisomerase II inhibitors, microtubule active agents, e.g. paclitaxelor an epothilone, alkylating agents, antiproliferative antimetabolites,such as gemcitabine or capecitabine, platin compounds, such ascarboplatin or cis-platin, bisphosphonates, e.g. AREDIA® or ZOMETA®, andmonoclonal antibodies, e.g. against HER2, such as trastuzumab.

The structure of the active agents identified by code nos., generic ortrade names may be taken from the actual edition of the standardcompendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications). The corresponding contentthereof is hereby incorporated by reference.

The above-mentioned compounds, which can be used in combination with acompound of the formula (I), can be prepared and administered asdescribed in the art, such as in the documents cited above.

In the combination therapies of the invention, the compound of theinvention and the other therapeutic agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompound of the invention and the other therapeutic may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g. in the case of a kit comprisingthe compound of the invention and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (iii) in the patient themselves, e.g.during sequential administration of the compound of the invention andthe other therapeutic agent. Accordingly, the invention provides the useof a compound of formula (I) for treating a disease or conditionmediated by c-Met, wherein the medicament is prepared for administrationwith another therapeutic agent. The invention also provides the use ofanother therapeutic agent for treating a disease or condition mediatedc-Met, wherein the medicament is administered with a compound of formula(I).

Thus, the invention relates in a further embodiment to a combination,particularly a pharmaceutical composition) comprising a therapeuticallyeffective amount of a compound of formula (I) in free form or inpharmaceutically acceptable salt form and a second therapeuticallyactive agent, for simultaneous or sequential administration. Theadditional therapeutic agent is preferably selected from the groupconsisting of an anti-cancer agent; an anti-inflammatory agent.

The invention further relates to a method for the treatment of a diseaseor disorder which responds to a c-Met tyrosine kinase, especially aproliferative disorder or disease, in particular a cancer, said methodcomprises administration of an effective amount of a combination ofpharmaceutical agents which comprise: (a) a compound of formula (I); and(b) one or more pharmaceutically active agents, to a subject in needthereof, especially human.

The invention further relates to the use of a combination ofpharmaceutical agents which comprise: (a) a compound of formula (I); and(b) one or more pharmaceutically active agents for the treatment of adisease or disorder which responds to a c-Met tyrosine kinase,especially a proliferative disorder or disease, in particular a cancer.

The invention further relates to the use of a combination ofpharmaceutical agents which comprise: (a) a compound of formula (I); and(b) one or more pharmaceutically active agents for the manufacture of amedicament for the treatment of a disease or disorder which responds toa c-Met tyrosine kinase, especially a proliferative disorder or disease,in particular a cancer.

The invention further relates to pharmaceutical compositions comprising(a) a compound of formula (I) and (b) a pharmaceutically active agent;and (c) a pharmaceutically acceptable carrier; wherein at least onepharmaceutically active agent is an anti-cancer therapeutic.

The present invention further relates to a commercial package or productcomprising: (a) a compound of formula (I); and (b) a pharmaceuticalformulation of a pharmaceutically active agent for simultaneous,concurrent, separate or sequential use; wherein at least onepharmaceutically active agent is an anti-cancer therapeutic.

Also combinations of two or more of sequential, separate andsimultaneous administration are possible, preferably such that thecombination component-drugs show a joint therapeutic effect that exceedsthe effect found when the combination component-drugs are usedindependently at time intervals so large that no mutual effect on theirtherapeutic efficiency can be found, a synergistic effect beingespecially preferred.

The invention also provides the use of a compound of formula (I) fortreating a disease or condition mediated by c-Met, wherein the patienthas previously (e.g. within 24 hours) been treated with anothertherapeutic agent. The invention also provides the use of anothertherapeutic agent for treating a disease or condition mediated by c-Met,wherein the patient has previously (e.g. within 24 hours) been treatedwith a compound of formula (I).

The term “delay of progression” as used herein means administration ofthe combination to patients being in a pre-stage or in an early phase,of the first manifestation or a relapse of the disease to be treated, inwhich patients, e.g., a pre-form of the corresponding disease isdiagnosed or which patients are in a condition, e.g., during a medicaltreatment or a condition resulting from an accident, under which it islikely that a corresponding disease will develop.

The term “Jointly therapeutically active” or “joint therapeutic effect”means that the compounds may be given separately (in a chronicallystaggered manner, especially a sequence-specific manner) in such timeintervals that they preferably, in the warm-blooded animal, especiallyhuman, to be treated, still show a (preferably synergistic) interaction(joint therapeutic effect). A joint therapeutic effect can, inter alia,be determined by following the blood levels, showing that both compoundsare present in the blood of the human to be treated at least duringcertain time intervals.

The term “Pharmaceutically effective” preferably relates to an amountthat is therapeutically or in a broader sense also prophylacticallyeffective against the progression of a disease or disorder as disclosedherein.

The term “a commercial package” or “a product”, as used herein definesespecially a “kit of parts” in the sense that the components (a) and (b)as defined above can be dosed independently or by use of different fixedcombinations with distinguished amounts of the components (a) and (b),i.e., simultaneously or at different time points. Moreover, these termscomprise a commercial package comprising (especially combining) asactive ingredients components (a) and (b), together with instructionsfor simultaneous, sequential (chronically staggered, in time-specificsequence, preferentially) or (less preferably) separate use thereof inthe delay of progression or treatment of a proliferative disease. Theparts of the kit of parts can then, e.g., be administered simultaneouslyor chronologically staggered, that is at different time points and withequal or different time intervals for any part of the kit of parts. Verypreferably, the time intervals are chosen such that the effect on thetreated disease in the combined use of the parts is larger than theeffect which would be obtained by use of only any one of the combinationpartners (a) and (b) (as can be determined according to standardmethods. The ratio of the total amounts of the combination partner (a)to the combination partner (b) to be administered in the combinedpreparation can be varied, e.g., in order to cope with the needs of apatient sub-population to be treated or the needs of the single patientwhich different needs can be due to the particular disease, age, sex,body weight, etc. of the patients. Preferably, there is at least onebeneficial effect, e.g., a mutual enhancing of the effect of thecombination partners (a) and (b), in particular a more than additiveeffect, which hence could be achieved with lower doses of each of thecombined drugs, respectively, than tolerable in the case of treatmentwith the individual drugs only without combination, producing additionaladvantageous effects, e.g., less side effects or a combined therapeuticeffect in a non-effective dosage of one or both of the combinationpartners (components) (a) and (b), and very preferably a strongsynergism of the combination partners (a) and (b).

Both in the case of the use of the combination of components (a) and (b)and of the commercial package, any combination of simultaneous,sequential and separate use is also possible, meaning that thecomponents (a) and (b) may be administered at one time pointsimultaneously, followed by administration of only one component withlower host toxicity either chronically, e.g., more than 3-4 weeks ofdaily dosing, at a later time point and subsequently the other componentor the combination of both components at a still later time point (insubsequent drug combination treatment courses for an optimal effect) orthe like.

In another embodiment of the invention, there is provided a method ofmanufacturing a compound of formula (I) and intermediates thereof. Acompound of the formula (I) may be prepared by processes that, thoughnot applied hitherto for the new compounds of the present inventionwhere they thus form new processes, are known per se. The schemesprovide a general overview of synthetic strategies to obtain a compoundof formula (I). All methods described can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g. “such as”) provided herein is intended merely to betterilluminate the invention and does not pose a limitation on the scope ofthe invention otherwise claimed.

Thus, the invention relates in a further aspect to a manufacturingprocess (a method for manufacturing) a compound of formula (I)comprising at least one reaction step as disclosed herein, andintermediates thereof.

Z₁ is selected from Cl, Br and I

Scheme 2 provides details for a synthetic strategy to obtain preferredcompounds of formula (IA, IB, IC) through (IIA, IIB and IIC)

Z₁ and Z₂ are independently selected from Cl, Br and I

Scheme 3 provides details for a synthetic strategy to obtain preferredcompounds of formula (ID) through (IID).

Z₁ is selected from Cl, Br and I

Scheme 4 provides details for a synthetic strategy to obtain preferredcompounds of formula (IE) through (IIE).

Z₁ is selected from Cl, Br and I

Scheme 5 provides details for a synthetic strategy to obtain preferredcompounds of formula (IF) through (IIF).

Z₁ and Z₂ are independently selected from Cl, Br and I

Oxidation using methods well known to the skilled person results inSO/SO₂ linkers

Scheme 6 provides details for a synthetic strategy to obtain preferredcompounds of formula (IG) and (IH) through (IIG) and (IIH) respectively.

Z₁ is selected from Cl, Br and I

Scheme 7 provides alternative details for a synthetic strategy to obtainpreferred compounds of formula (IH) through (IIH).

Scheme 8 provides details for a synthetic strategy to obtain preferredcompounds of formula (IK) through (IIK).

Z₁ is selected from Cl, Br and I

Scheme 9 provides details for a synthetic strategy to obtain preferredcompounds of formula (IL).

The following examples illustrate the invention without limiting thescope thereof. In the examples provided, temperatures are measured indegrees Celsius. Unless otherwise indicated, the reactions take place atroom temperature (rt). Further, if not indicated otherwise, theanalytical and preparative HPLC conditions are as follows:

Method A:

The flow is 0.5 mL/min of methanol and water (with 0.5% acetic acid)0-4.0 min: 10% to 90% of methanol4.0-6.0 min: 90% of methanolColumn: GP C18 3 μm 4.6×30 mm from Sepax.Oven temperature: 30° C.

Method B:

The flow is 1.2 mL/min of methanol and water (with 0.5% acetic acid)0-2.0 min: 10% to 90% of methanol2.0-3.0 min 90% of methanolColumn: GP C18 3 μm 4.6×30 mm from Sepax.Oven temperature: 30° C.

Method C:

The flow is 0.5 mL/min of methanol and water (with 0.5% acetic acid)0-3.0 min: 60% to 90% of methanol3.0-5.0 min: 90% of methanolColumn: GP C18 3 μm 4.6×30 mm from Sepax.Oven temperature: 30° C.

Method D:

The flow is 0.5 mL/min of methanol and water (with 0.5% acetic acid)0-3.0 min: 10% to 50% of methanol3.0-4.0 min: 50% of methanolColumn: GP C18 3 μm 4.6×30 mm from Sepax.Oven temperature: 30° C.

Method E:

The flow is 0.5 mL/min of methanol and water (with 0.5% acetic acid)0-4.0 min: 10% to 90% of methanol4.0-8.0 min: 90% of methanolColumn: GP C18 3 μm 4.6×30 mm from Sepax.Oven temperature: 30° C.

Method F:

The flow is 1 mL/min of Hexane/Ethanol/Diethyleamine 80/20/0.1, v/v/v

Column: AD-H

Oven temperature: 25° C.

Method G:

The flow is 1 mL/min of Hexane/Ethanol/Diethyleamine 70/30/0.1, v/v/v

Column: AD-H

Oven temperature: 25° C.

Method H:

The flow is 1 mL/min of Hexane/Isopropanol/Diethylamine 70/30/0.1, v/v/v

Column: CHIRALPAK OD-H

Oven temperature: 25° C.

Method I:

SFC equipment: Thar SFC Prep 80The flow is 45 g/min of Methanol/CO₂ 70/30

Column: CHIRALPAK OD-H, 2.0×25 cm

Wave length: UV 254 nmOven temperature: 35° C.

Method J:

The flow is 1.2 mL/min of methanol and water (with 0.5% acetic acid)0-3.0 min: 60% to 90% of methanolColumn: GP C18 3 μm 4.6×30 mm from Sepax.Oven temperature: 30° C.

Method K

The flow is 1 mL/min of Hexane/Ethanol/Diethyleamine 80/20/0.1, v/v/v

Column: OJ-H

Oven temperature: 25° C.

Method L

SFC equipment: Thar SFC Prep 80The flow is 45 g/min of Methanol/CO₂ 75/25

Column: CHIRALPAK AD-H, 2.0×25 cm

Wave length: UV 254 nmOven temperature: 35° C.

In the following examples, the abbreviations given below are used:

-   AcOH acetic acid-   aq. aqueous-   atm. atmosphere-   BINAP 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl-   Bn benzyl-   Boc tert-butoxycarbonyl-   DCC dicyclohexylcarbodiimide-   DCM dichloromethane-   DME 1,2-dimethoxyethane-   Et₂O diethyl ether-   EtOAc or EA ethyl acetate-   EtOH ethanol-   DME dimethyl ethylene glycol-   DMF N,N-dimethylformamide-   DMSO dimethyl sulfoxide-   eq. equivalent(s)-   h hour(s)-   HATU 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate-   HPLC High Performance Liquid Chromatography-   HV high vacuum-   IBX 2-iodoxybenzoic acid-   Isolute Isolute® HM-N by International Solvent Technology Ltd., U.K.-   LAH lithium aluminium hydride-   LCMS liquid chromatography coupled with mass spectrometry-   LDA lithium diisopropylamide-   mL milliliter(s)-   min minute(s)-   MPLC Medium Pressure Liquid Chromatography-   MS-ES electrospray mass spectrometry-   MW microwave-   NBS N-bromosuccinimide-   n-BuLi n-butyllithium-   NMP N-methylpyrrolidinone-   PdCl₂(dppf) 1,1-bis(diphenylphosphino)ferrocenedichloropalladium    (II)-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium (0)-   PdCl₂(Ph₃)₂ dichlorobis(triphenylphosphine)palladium (II)-   R_(f) ratio of fronts in TLC-   rt room temperature-   TBAF tetrabutylammonium fluoride-   TBME methyl tert-butyl ether-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TLC thin layer chromatography-   t_(R) retention time-   UV Ultraviolet

Syntheses of Intermediates Intermediate A3-Bromo-6-chloroimidazo[1,2-b]pyridazine

To a solution of 6-chloroimidazo[1,2-b]pyridazine (5 g, 32.6 mmol) inacetonitrile (300 mL) was added NBS (6.37 g, 35.8 mmol) and TFA (0.75mL). The resulting solution was allowed to stir at it overnight. Thesolvents were removed under reduced pressure and the residue wasdissolved in EtOAc, washed with NaHCO₃ solution, water and brine, driedover Na₂SO₄ and concentrated in vacuo to afford 7.2 g (92%) of the titlecompound as a light yellow solid. ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.91 (d,1H), 7.79 (s, 1H), 7.12 (d, 1H). LCMS (method A): [MH]⁺=232/234,t_(R)=4.48 min.

Intermediate B 2-(2,3-Dihydroxypropoxy)isoindoline-1,3-dione and2-(1,3-dihydroxypropan-2-yloxy)isoindoline-1,3-dione

To a solution of glycerol in THF containing phthalimide and PPh₃ wasadded DIAD at 0° C. After being stirred for 20 h at rt, the mixture wasconcentrated under reduced pressure. Then water was added and theaqueous solution was extracted with DCM. The combined organic layerswere dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography (2% MeOH in DCM) to affordthe title compound (1:1 mixture) as a white solid. LCMS (method A):[MH]⁺=238, t_(R)=3.39/3.46 min.

Intermediate C 1-Methyl-1H-indazole-5-carbaldehyde

5-Bromo-1H-indazole (i)

A suspension of 5-bromo-2-fluorobenzaldehyde (10.15 g, 50 mmol),MeONH₂—HCl (4.07 g, 50 mmol) and K₂CO₃ (7.59 g, 55.0 mmol) in 100 mL ofDMF was stirred at 40° C. for 5 h. The mixture was filtered. Thefiltrate containing the oxime intermediate was concentrated in vacuo togive approximately 50 mL of residue. To this concentrated oxime residuewas added N₂H₄—H₂O (50 mL, 1.03 mol) and the mixture was heated atreflux overnight. After the reaction was complete, the reaction mixturewas concentrated in vacuo. The residue was diluted with water andextracted with EtOAc twice. The organic layers were combined, dried overNa₂SO₄ and concentrated. The crude product was purified by flashchromatography (hexane:EtOAc=10:1) to afford the title compound as awhite solid (6.02 g, 61.2%). ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 13.24 (bs,1H), 9.85 (s, 1H), 8.05 (s, 1H), 7.99 (s, 1H), 7.52 (d, 1H), 7.44 (dd,1H). LCMS (method A): [MH]⁺=1971199, t_(R)=4.94 min.

5-Bromo-1-methyl-1H-indazole (ii) and 5-Bromo-2-methyl-2H-indazole (iii)

To a solution of 5-bromo-1H-indazole (0.19 g, 0.94 mmol) in 3 mL of THFat 0° C. was added NaH (0.04 g, 1.03 mmol). The reaction mixture wasstirred at this temperature for 1 h before the addition of methyl iodide(0.09 mL, 1.41 mmol) at 0° C. The reaction was allowed to warm to itslowly and stirred for 2 h, quenched with water and concentrated invacuo. The residue was diluted with water and extracted with DCM twice.The organic layers were combined, dried over Na₂SO₄ and concentrated.The crude products were purified by flash chromatography(hexane:EtOAc=10:1) to give the title compound ii (88.7 mg, 42.5%) andiii (60.9 mg, 29%) as white solid. ii: ¹H-NMR (400 MHz, DMSO-d₆) ppm8.02 (d, 1H), 7.99 (d, 1H), 7.64 (d, 1H), 7.50 (dd, 1H), 4.04 (s, 3H).LCMS (method A): [MH]⁺=211/213, t_(R)=5.19 min. iii: ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.33 (s, 1H), 7.95 (d, 1H), 7.57 (d, 1H), 7.30 (dd, 1H),4.16 (s, 3H). LCMS (method A): [MH]⁺=211/213, t_(R)=4.95 min.

1-Methyl-1H-indazole-5-carbaldehyde (Intermediate C)

A suspension of n-BuLi (7.33 mL, 11.73 mmol) and ethylmagnesium bromide(5.76 mL, 5.76 mmol) in toluene (30 mL) was stirred at −30° C. for 30min, and then a solution of 5-bromo-1-methyl-1H-indazole (2.25 g, 10.66mmol) in THF (5 mL) was added. After 1 h, anhydrous DMF (4.95 mL, 64.0mmol) was added at −10° C. The reaction mixture was allowed to warm tort and stirred for 2 h. The reaction was quenched with saturated aqueousNH₄Cl solution and concentrated in vacuo. The residue was diluted withwater, extracted with DCM twice. The organic layers were combined, driedover Na₂SO₄ and concentrated. The crude product was purified by flashchromatography (hexane:EtOAc=10:1) to give the title compound as a whitesolid (1.37 g, 76%). ¹H-NMR (400 MHz, DMSO-d₆) δ ppnn 10.02 (s, 1H),8.41 (d, 1H), 8.31 (d, 1H), 7.86 (dd, 1H), 7.78 (d, 1H), 4.09 (s, 3H).LCMS (method A): [MH]⁺=161, t_(R)=4.00 min.

Intermediate D Quinolin-6-ylmethanamine

Quinolin-6-ylmethanol (i)

To a solution of methyl quinoline-6-carboxylate (14 g, 74.8 mmol) in THF(80 mL) was added

LiAlH₄ (2.84 g, 74.8 mmol) in portions. The reaction was stirred at rtfor 20 min. Then water (2.84 mL) and aqueous NaOH (10%, 4.26 mL) wereadded dropwise to quench the reaction. After stirring for additional 20min, ether was added and the resulting mixture was filtered throughcelite. The filtrate was concentrated in vacuo to give a residue whichwas purified by column chromatography with hexane/EtOAc to affordquinolin-6-ylmethanol (7.6 g, 64%).

2-(Quinolin-6-ylmethyl)isoindoline-1,3-dione (ii)

To a solution of isoindoline-1,3-dione (6.47 g, 44.0 mmol) andtriphenylphosphine (11.53 g, 44.0 mmol) in THF (70 mL) at 0° C. wasadded a solution of quinolin-6-ylmethanol (7 g, 44.0 mmol) in THF (30mL) and (E)-diisopropyl diazene-1,2-dicarboxylate (8.89 g, 44.0 mmol)dropwise over a period of 30 min. The mixture was heated at 30° C. andkept stirring for 20 h. After cooling and concentration, the resultingresidue was purified by Analogix silica gel with gradient hexanes/EtOActo provide 2-(quinolin-6-ylmethyl)isoindoline-1,3-dione (12.04 g, 95%).LCMS (method A): [MH]⁺=289, t_(R)=4.89 min.

Quinolin-6-ylmethanamine (Intermediate D)

To a solution of 2-(quinolin-6-ylmethyl)isoindoline-1,3-dione (20 g,69.4 mmol) in MeOH (100 mL) was added hydrazine monohydrate (3.47 g,69.4 mmol). The solution was heated at reflux for 3 h, then cooled to itand filtered through celite. The filtrate was concentrated in vacuo.EtOAc then was added to the residue and the resulting solution wasfiltered and concentrated in vacuo to afford 5 g (41%) of the titlecompound. LCMS (method B): [MH]⁺=159, t_(R)=0.93 min.

Intermediate E and F 7-Fluoro-quinoline-6-carbaldehyde and7-(7-fluoro-quinolin-6-yl)-methylamine

6-Bromo-7-fluoro quinoline (i)

To a suspension of 4-bromo-3-fluoro-phenylamine (100.0 g, 526 mmol) inconcentrated sulfuric acid (290 mL) was added glycerol (220.0 g, 2.39mol, 4.5 eq.) followed by ferrous sulfate (30.0 g, 0.2 eq.). Thereaction mixture was heated at 130° C. for 14 h, cooled to it and pouredonto ice-water. The solution was adjusted with saturated aqueousammonium hydroxide to pH 8 and extracted with DCM (2 L×3). The combinedorganic layers were washed with brine (1 L×3), dried over Na₂SO₄ andconcentrated under reduced pressure to afford a crude product, which waspurified by column chromatography (petroleum:EtOAc=10:1) to give thetitle compound as white solid (45 g, 39%). ¹H-NMR (400 MHz, DMSO-d₆) δppm 8.86 (s, 1H), 8.56 (m, 1H), 8.45 (m, 1H), 7.90 (d, 1H), 7.71 (m,1H).

7-Fluoro-quinoline-6-carbaldehyde (Intermediate E)

To a suspension of Pd(PPh₃)₄ (1.27 g, 1.1 mmol) and sodium formate (13.8g, 132 mmol, 6 eq.) in acetonitrile (30 mL) was added a solution of6-bromo-7-fluoro quinoline (5 g, 22 mmol) in DMSO (30 mL). The reactionmixture was heated at 120° C. under a CO atmosphere (1 MPa) for 4 h,cooled to it and concentrated under reduced pressure. The residue waspartitioned between water (100 mL) and EtOAc (150 mL). The organic layerwas separated, washed with brine (100 mL), dried over Na₂SO₄ andconcentrated under reduced pressure to give a residue, which waspurified by column choromatography with gradient petroleum:EtOAc from10:1 to 3:1 to give the title compound as a white solid (400 mg, 10.4%).¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.95 (s, 1H), 8.46 (m, 1H), 8.20 (m,1H), 7.75 (d, 1H), 7.53 (m, 1H).

7-(7-Fluoro-quinolin-6-yl)-methylamine (Intermediate F)

7-Fluoro-quinoline-6-carbaldehyde (500 mg, 2.85 mmol) was dissolved inan ammonia solution (2 M in methanol, 50 mL). After stirring at it for 3h, NaBH₄ (108.0 mg, 2.85 mmol) was added in portions. The reaction wasstirred overnight, quenched by water in an ice-bath. After removal ofmethanol under reduced pressure, the residue was diluted with water,adjusted its pH to around 8 with 1N HCl solution, and extracted with DCMthree times. The combined organic layers were washed with water anddried over Na₂SO₄, filtered and concentrated in vacuo. The crude productwas purified by chromatography (DCM:MeOH=50:1) to give the titlecompound as a yellow solid (250.0 mg, 49%). ¹H-NMR (400 MHz, DMSO-d₆) δppm 8.86 (dd, 1H), 8.36 (d, 1H), 8.07 (d, 1H), 7.68 (d, 1H), 7.49 (dd,1H), 3.93 (s, 2H), 1.98 (s, 2H).

Intermediate G O-(4-Methoxybenzyl)hydroxylamine

(i)

To a solution of 2-hydroxyisoindoline-1,3-dione (1.0 g, 6.13 mmol) inDMSO (10 mL) was added Cs₂CO₃ (1.997 g, 6.13 mmol). The resultingmixture was stirred at it for 30 min. 1-bromomethyl 4-methoxy-benzene(0.88 mL, 6.13 mmol) was then added dropwise. After stirring at 50° C.overnight, the reaction mixture was quenched with NH₄Cl (aq), extractedwith EtOAc, washed with NH₄Cl (aq), dried over Na₂SO₄, filtered andconcentrated in vacuo to give a crude product, which was purified bysilica gel column with gradient hexanes:EtOAc to give2-(benzyloxy)isoindoline-1,3-dione as a white solid (0.9 g, 49%). ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 7.85 (s, 4H), 7.42 (d, 2H), 6.94 (d, 2H), 5.08(s, 2H), 3.75 (s, 3H).

O-(4-Methoxybenzyl)hydroxylamine (Intermediate G)

To a solution of 2-(4-methoxybenzyloxy)isoindoline-1,3-dione (200 mg,0.706 mmol) in MeOH (5 mL) was added hydrazine monohydrate (35.3 mg,0.706 mmol). The reaction mixture was stirred at 65° C. for 1 h. Thesolvent was removed in vacuo, and the resulting residue was diluted withEtOAc (5 mL). After stirring for 20 min, the mixture was filtered. Thefiltrate was concentrated in vacuo to afford the title compound. ¹H-NMR(400 MHz, CDCl₃) δ ppm 7.30 (m, 2H), 6.90 (m, 2H), 4.63 (m, 2H), 3.81(s, 3H).

Intermediate H O-Benzylhydroxylamine

2-(Benzyloxy)isoindoline-1,3-dione (i)

The title compound was prepared from 2-hydroxyisoindoline-1,3-dione and(bromomethyl)benzene in 64% yield using the same procedure as describedin the synthesis of intermediate G. LCMS (method A): [MH]⁺=254,t_(R)=5.19 min.

O-Benzylhydroxylamine (Intermediate H)

The title compound was prepared from 2-(benzyloxy)isoindoline-1,3-dioneand hydrazine monohydrate in 64% yield using the same procedure asdescribed in the synthesis of intermediate G. ¹H-NMR (400 MHz, CDCl₃) δppm 7.37 (m, 5H), 6.70 (s, 2H).

Intermediate I t-Butyl 4-(aminooxy)piperidine-1-carboxylate

t-Butyl 4-(1,3-dioxoisoindolin-2-yloxy)piperidine-1-carboxylate (i)

To a solution of t-butyl 4-hydroxypiperidine-1-carboxylate (250 mg,1.242 mmol) was added triphenylphosphine (326 mg, 1.242 mmol) and2-hydroxyisoindoline-1,3-dione (203 mg, 1.242 mmol). After stirring atrt for 10 min, (E)-diisopropyl diazene-1,2-dicarboxylate (251 mg, 1.242mmol) was added. After stirring at 30° C. overnight, the reactionmixture was quenched with NH₄Cl (aq), extracted with EtOAc, washed withNH₄Cl (aq), dried over Na₂SO₄, filtered and concentrated in vacuo togive a crude product, which was purified by silica gel column withgradient hexanes:EtOAc to give the title compound as a colorless oil(252 mg, 59%). LCMS (method B): [MNa]⁺=369, t_(R)=2.59 min.

t-Butyl 4-(aminooxy)piperidine-1-carboxylate (Intermediate I)

The title compound was prepared from tert-butyl4-(1,3-dioxoisoindolin-2-yloxy)piperidine-1-carboxylate and hydrazinemonohydrate in 85% yield using the same procedure as described in thesynthesis of intermediate G

Intermediate J t-Butyl 4-(aminooxymethyl)piperidine-1-carboxylate

t-Butyl 4-((1,3-dioxoisoindolin-2-yloxy)methyl)piperidine-1-carboxylate(i)

The title compound was prepared from t-butyl4-(hydroxymethyl)piperidine-1-carboxylate and2-hydroxyisoindoline-1,3-dione in 80% yield using the same procedure asdescribed in the synthesis of intermediate B. LCMS (method B):[MNa]⁺=383, t_(R)=2.64 min.

t-Butyl 4-(aminooxymethyl)piperidine-1-carboxylate (Intermediate J)

The title compound was prepared from t-butyl4-((1,3-dioxoisoindolin-2-yloxy)methyl)-piperidine-1-carboxylate andhydrazine monohydrate in 85% yield using the same procedure as describedin the synthesis of intermediate B.

Intermediate K Methyl 2-(aminooxy)acetate

Methyl 2-(1,3-dioxoisoindolin-2-yloxy)acetate (i)

The title compound was prepared from 2-hydroxyisoindoline-1,3-dione andmethyl 2-bromoacetate in 56% yield using the same procedure as describedin the synthesis of intermediate G. LCMS (method B): [MH]⁺=236,t_(R)=1.82 min.

Methyl 2-(aminooxy)acetate (Intermediate K)

The title compound was prepared from methyl2-(1,3-dioxoisoindolin-2-yloxy)acetate and hydrazine monohydrate in 67%yield using the same procedure as described in the synthesis ofintermediate G.

Intermediate L 5-Bromo-6-fluoro-1-methyl-1H-indazole

To a solution of 5-bromo-6-fluoro-1H-indazole (4 g, 18.60 mmol) in DMF(20 mL) was added potassium 2-methylpropan-2-olate (2.087 g, 18.60mmol). The resulting mixture was stirred for 40 min. CH₃I (3.17 g, 22.32mmol) was added dropwise. After stirring overnight, the reaction mixturewas quenched with NH₄Cl (aq), extracted with EtOAc, washed with NH₄Cl(aq), dried over Na₂SO₄, filtered and concentrated in vacuo to give acrude product, which was purified with silica gel column chromatographywith gradient hexanes:EtOAc to give5-bromo-6-fluoro-1-methyl-1H-indazole (1.86 g, 42%) as light yellowsolid.

Intermediate M 1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethanone

N′-(6-Chloro-pyridazin-3-yl)-N,N-dimethyl-formamidine (i)

A mixture of 3-amino-6-chloropyridazine (1.3 g, 10 mmol) anddimethylformamide dimethylacetal (1.35 mL, 10.2 mmol) was heated atreflux for 2 h and concentrated in vacuo to afford a brown solid. Afterrecrystallization with EtOAc, 1.5 g ofN′-(6-chloro-pyridazin-3-yl)-N,N-dimethyl-formamidine was obtained in81% yield.

1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethanone (Intermediate M)

To a solution of N′-(6-chloro-pyridazin-3-yl)-N,N-dimethyl-formamidine(1.3 g, 7 mmol) in DMF (60 mL) was added NaI (1 g, 6.7 mmol) andchloroacetone (1 mL, 12.6 mmol). The mixture was heated at 80° C.overnight and concentrated under reduced pressure. The residue waspurified by column chromatography to afford1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethanone (0.7 g) in 51% yield.¹H-NMR (400 MHz, CDCl₃) δ ppm 8.42 (s, 1H), 8.05 (d, 1H), 7.31 (d, 1H),2.77 (s, 3H).

Intermediate N 6-Chloro-imidazo[1,2-b]pyridazine-3-carbaldehyde

(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-methanol (i)

To a solution of 6-chloroimidazo[1,2-b]pyridazine (1.5 g, 9.8 mmol) inAcOH (50 mL) was added NaOAc (1.4 g, 17.1 mmol) and paraformaldehyde(1.5 g). The mixture was heated at reflux overnight and concentratedunder reduced pressure. The residue was basified to pH 12. Then themixture was filtered and the solid was washed with EtOH to afford(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-methanol (1.3 g) in 72% yield.

6-Chloro-imidazo[1,2-b]pyridazine-3-carbaldehyde (Intermediate N)

To a solution of (6-chloro-imidazo[1,2-b]pyridazin-3-yl)-methanol (1.3g, 7.1 mmol) in DCM (50 mL) was added active MnO₂ (3 g, 34.5 mmol). Themixture was stirred at rt overnight and filtered. The filtrate wasconcentrated under vacuum and the residue was washed with EtOAc toaffrode 6-chloro-imidazo[1,2-b]pyridazine-3-carbaldehyde (0.7 g) in 54%yield. ¹H-NMR (400 MHz, CDCl₃) δ ppm 10.36 (s, 1H), 8.42 (s, 1H), 8.08(d, 1H), 7.38 (d, 1H).

Intermediate O6-((6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline

3-Chloro-6-hydrazinylpyridazine (i)

A solution of 3,6-dichloropyridazine (3 g, 20.14 mmol) and hydrazinemonohydrate (1 g, 20.14 mmol) in 20 mL THF in a sealed tube was heatedat 80° C. for 5 h. Solvent was evaporated and the crude was used in thenext step without purification (3.56 g, 100%). LCMS (method B):[MH]⁺=145.1, t_(R)=0.574 min.

N′-(6-Chloropyridazin-3-yl)-2-(quinolin-6-yl)acetohydrazide (ii)

To a suspension of 3-chloro-6-hydrazinylpyridazine (3 g, 20.75 mmol) and2-(quinolin-6-yl)acetic acid (4.27 g, 22.83 mmol) in DCM (200 mL) wasadded DCC (5.14 g, 24.90 mmol). The solution was stirred at it overweekend. The title compound as a white solid containing somedicyclohexyl urea was collected and used in the next step withoutfurther purification (8 g, 100%). LCMS (method A): [MH]⁺=314.1,t_(R)=2.851 min.

6-((6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline(intermediate O)

A solution ofN′-(6-chloropyridazin-3-yl)-2-(quinolin-6-yl)acetohydrazide (8 g crude,25.5 mmol) in 250 mL of acetic acid was heated at 50° C. for 5 h. Afterthe reaction was complete, the solvent was evaporated and the residuewas taken up in EtOAc. The formed solid (mainly dicyclohexyl urea) wasfiltered off and the filtrate was evaporated to afford the titlecompound as yellow solid (4 g, 53%). ¹H-NMR (400 MHz, MeOH-d₄) δ ppm8.82 (d, 1H), 8.33 (d, 1H), 8.25 (d, 1H), 8.0 (d, 1H), 7.93 (s, 1H),7.83 (d, 1H), 7.53 (m, 1H), 7.42 (d, 1H), 4.79 (s, 2H). LCMS (method B):[MH]⁺=296.0, t_(R)=1.876 min.

Intermediate P 4,6-Difluoro-1-methyl-1H-indazole

N-Methyl-N′-[1-(2,4,6-trifluoro-phenyl)-meth-(E)-ylidene]-hydrazine (i)

A solution of 2,4,6-trifluorobenzaldehyde (3 g, 18.74 mmol) and methylhydrazine (40% in water, 2.6 mL, 18.74 mmol) in 20 mL of anhydrousethanol was stirred at rt for 1 h. Solvent was evaporated to give thecrude title compound as a white solid which was used in the next stepwithout purification (3.95 g, 100%). LCMS (method B): [MH]⁺=189,t_(R)=2.16 min.

4,6-Difluoro-1-methyl-1H-indazole (Intermediate P)

N-Methyl-N′-[1-(2,4,6-trifluoro-phenyl)-meth-(E)-ylidene]-hydrazine(3.85 g, 20.46 mmol) was heated in a seaed tube at 210° C. for 2 h.After cooling, the black residue was dissovled in DCM and purified byflash chromatography (EtOAc:hexane 10:90) to give the title compound asa light yellow crystal (1.926 g, 56%). ¹H-NMR (400 MHz, MeOH-d₄) δ ppm8.05 (s, 1H), 7.16 (d, 1H), 6.75 (t, 1H), 3.32 (s, 3H). LCMS (method B):[MH]⁺=169, t_(R)=2.28 min.

Intermediate Q 2-(Aminooxy)propan-1-ol

Ethyl 2-(tert-butoxycarbonylaminooxy)propanoate (i)

To a solution of t-butyl hydroxycarbamate (530 mg, 3.98 mmol) andpotassium hydroxide (223 mg, 3.98 mmol) in EtOH (10 mL) was added ethyl2-bromopropanoate (600 mg, 3.31 mmol) slowly at rt. The reaction mixturewas heated at reflux overnight. White precipitate was filtered off andthe filtrate was concentrated. The resulting residue was dissolved inether, washed with water and brine, and dried over Na₂SO₄. Solvent wasevaporated to afford the title compound as a clear oil which was used inthe next step without further purification (825 mg, 100%). ¹H-NMR (400MHz, CDCl₃) δ ppm 7.62 (s, 1H), 4.46 (q, 1H), 4.24 (q, 2H), 1.46 (d,3H), 1.48 (s, 9H), 1.28 (t, 3H).

t-Butyl 1-hydroxypropan-2-yloxycarbamate (ii)

A solution of LiAlH₄ (213 mg, 5.62 mmol) in anhydrous THF (8 mL) wasadded slowly to a solution of ethyl2-(t-butoxycarbonylaminooxy)propanoate (820 mg, 3.52 mmol) in THF (15mL) at 0° C. The mixture was stirred at 0° C. for 5 h and then at rtovernight. The solution was quenched with a mixture of Na₂SO₄ and water,and stirred for an additional 1.5 h. The mixture was filtered andconcentrated. The crude was dissolved in EtOAc, washed with water andbrine, and then dried over Na₂SO₄. Solvent was evaporated to afford thetitle compound as a clear oil (500 mg, 74.4%). ¹H-NMR (400 MHz, CDCl₃) δppm 7.09 (s, 1H), 3.95 (m, 1H), 3.69 (dd, 1H), 3.47 (m, 1H), 1.51 (s,9H), 1.21 (d, 3H).

2-(Aminooxy)propan-1-ol (Intermediate Q)

To a solution of t-butyl 1-hydroxypropan-2-yloxycarbamate (500 mg, 2.61mmol) in DCM (15 mL) was added 3 mL of HCl in dioxane. The solution wasthen stirred at rt overnight. Solvent was evaporated to provide thetitle compound as HCl salt (365 mg, 98%, purity 90%). ¹H-NMR (400 MHz,MeOH-d₄) δ ppm 4.28 (m, 1H), 3.80 (m, 1H), 3.70 (m, 1H), 1.23 (d, 3H).

Intermediate R6-[(6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-difluoro-methyl]-quinoline

Difluoro-quinolin-6-yl-acetic acid ethyl ester (i)

Sodium iodide (4.32 g, 28.8 mmol), copper (I) iodide (137 mg, 0.72mmol), 6-bromo-quinoline (3 g, 14.4 mmol), N,N′-dimethyl-cyclohexane(0.227 mL, 1.44 mmol) and dioxane were charged in a microwave tube (25mL). The tube was purged with nitrogen for 10 min and sealed with aTeflon septum. The reaction mixture was stirred at 110° C. for 15 h.After cooling, the mixture was poured onto ice-water and extracted withDCM. The crude was purified by silica gel column to give6-iodo-quinoline as light green solid (3.5 g, 92%).

To a suspension of 6-iodo-quinoline (1.0 g, 4 mmol) and Cu(0) (559 mg,8.8 mmol) in dry DMSO was added bromodifluoro-acetic acid ethyl ester(893 mg, 4.4 mmol). The reaction mixture was stirred under N₂ at 55° C.for 15 h. The mixture was poured in a solution of K₂CO₃ and extractedwith EtOAc. The organic layer was collected and dried over MgSO₄. Thecrude was purified by silica gel column to give the title compound as ared oil (310 mg, 30%). ¹H-NMR (400 MHz, CDCl₃) δ ppm 1.33 (t, 3H), 4.334(q, 2H), 7.52 (m, 1H), 7.93 (m, 1H), 8.15 (s, 1H), 8.20-8.23 (m, 2H),9.03 (s, 1H).

Difluoro-quinolin-6-yl-acetic acid hydrazide (ii)

Difluoro-quinolin-6-yl-acetic acid ethyl ester (836 mg, 3.33 mmol) wasdissolved in MeOH (13 mL). Hydrazine monohydrate (1.5 mL, 16.8 mmol) wasadded. The mixture was heated at 45° C. for 30 min, cooled to rt,concentrated, and taken up in DCM. The organic layer was dried overMgSO₄, filtered and concentrated in vacuo to give a crude product, whichwas purified by silica gel column to give the title compound as lightorange solid (400 mg, 51%). ¹H-NMR (400 MHz, CDCl₃). ppm 3.99 (br s,2H), 7.51 (m, 1H), 7.92 (m, 1H), 8.15 (s, 1H), 8.20-8.26 (q, 2H), 9.02(m, 1H).

6-[(6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-difluoro-methyl]-quinoline(Intermediate R)

3,6-Dichloropyridazine (160 mg, 1.07 mmol) anddifluoro-quinolin-6-yl-acetic acid hydrazide (254 mg, 1.07 mmol) wereadded in n-BuOH (20 mL). The reaction mixture was heated at 130° C. for12 h. The solvent was removed under reduced pressure. The crude waspartitioned in aqueous solution of K₂CO₃ and EtOAc. The organic layerswere combined and concentrated to give a solid, which was purified bysilica gel column to give the title compound as black solid (190 mg,53%). ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 7.62 (m, 2H), 7.90 (m, 1H), 8.22(m, 1H), 8.35 (m, 1H), 8.65 (m, 2H), 9.02 (m, 1H).

Intermediate S 2-(Aminooxy)ethanol hydrochloride

t-Butyl 2-hydroxyethoxycarbamate hydrochloride (I)

The title compound was prepared according to the procedure described inWO2006/10094. To a mixture of t-butyl hydroxycarbamate (11.27 g, 85mmol) and DBU (12.8 mL, 85 mmol) was added 2-bromoethanol (15 mL, 212mmol) slowly, and the reaction mixture was stirred at 40° C. for 2.5days. After cooling, the reaction mixture was diluted with DCM, andwashed successively with cold 1N HCl aqueous solution, water, and brine.The organic layer was dried over anhydrous Na₂SO₄, purified by columnchromatography (38% EtOAc in hexane) to afford 12.6 g (70%) of the titlecompound as a colorless syrup. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.95 (sbr, 1H), 4.55 (t, 1H), 3.70 (t, 2H), 3.45-3.55 (m, 2H), 1.38 (s, 9H).

2-(Aminooxy)ethanol hydrochloride (Intermediate S)

To a solution of t-butyl 2-hydroxyethoxycarbamate hydrochloride (5.82 g,32.8 mmol) in dioxane (60 mL) was added concentrated HCl (3.5 mL)dropwise, and the reaction mixture was stirred at rt overnight. Solventwas removed to afford 3.78 g (100%) of the title compound as colorlesssyrup. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 10.93 (s br, 2H), 3.70-4.80 (sbr, 1H), 4.02 (t, 2H), 3.60 (t, 2H).

Intermediate T 3-(Aminooxy)propan-1-ol hydrochloride

The title compound was prepared using the same procedure as described inthe synthesis of intermediate S. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 10.89(s br, 2H), 3.85-4.50 (s br, 1H), 4.05 (t, 2H), 3.45 (t, 2H), 1.68-1.74(m, 2H).

Intermediate U O-(Oxetan-3-yl)hydroxylamine

2-(Oxetan-3-yloxy)isoindoline-1,3-dione (i)

To a solution of oxetan-3-ol (1.0 g, 13.50 mmol) were addedtriphenylphosphine (4.25 g, 16.20 mmol) and2-hydroxyisoindoline-1,3-dione (2.42 g, 14.85 mmol). After stirring atrt for 10 min, (E)-diisopropyl diazene-1,2-dicarboxylate (3.28 g, 16.20mmol) was added. After stirring at 30° C. overnight, the reactionmixture was quenched with NH₄Cl (aq), extracted with EtOAc, washed withNH₄Cl (aq), dried over Na₂SO₄, filtered and concentrated in vacuo togive the crude product, which was purified with column chromatography onsilica gel (gradient hexanes:EtOAc) to give a colorless oil2-(oxetan-3-yloxy)isoindoline-1,3-dione (400 mg, 6%). LCMS (method B):[MH]⁺=220, t_(R)=1.67 min.

O-(Oxetan-3-yl)hydroxylamine (Intermediate U)

To a solution of 2-(oxetan-3-yloxy)isoindoline-1,3-dione (220 mg, 1.0mmol) in MeOH (5 mL) was added hydrazine hydrate (50.4 mg, 1.0 mmol).The reaction was allowed to stir at 65° C. for 1 h. Solvent was removedin vacuo and the resulting residue was diluted with EtOAc (5 mL). Afterthe mixture was stirred for 20 min, the formed precipitate was filteredoff. The filtrate was concentrated in vacuo to afford the product.

Intermediate V 2-(1,3-Dioxoisoindolin-2-yloxy)acetamide

A solution of 2-hydroxyisoindoline-1,3-dione (2.4 g, 14.71 mmol),2-chloroacetamide (1.65 g, 17.65 mmol) and K₂CO₃ (2.44 g, 17.65 mmol) in40 mL of DMF was stirred at 90° C. overnight. The solid was removed byfiltration and the solution was concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel eluting withEtOAc/methanol gradient to afford the title compound. ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 7.89 (dd, 1H), 7.68-7.64 (m, 2H), 7.45-7.43 (m, 2H), 7.35(s, 1H), 4.23 (s, 2H). LCMS (method A): [MH]⁺=221, t_(R)=2.665 min.

Intermediate W1-(3-(Quinolin-6-ylmethyl)imidazo[1,2-a]pyrimidin-6-yl)ethanone (W)

6-((6-Bromoimidazo[1,2-a]pyrimidin-3-yl)methyl)quinoline (i)

A solution of 2-chloro-3-(quinolin-6-yl)propanal (1.0 g, 2.54 mmol) and5-bromopyrimidin-2-amine (0.53 g, 3.05 mmol) in 2-methyl-butan-2-ol (10mL) was stirred at 135° C. for 12 h. After cooling, the solvent wasremoved in vacuo and the residue was purified by flash chromatography insilica gel eluting with a CH₂Cl₂/MeOH gradient to afford a mixture ofthe title compound and6-(6-bromo-imidazo[1,2-a]pyrimidin-2-ylmethyl)quinoline (250 mg, 29%) asbrown solid. LCMS (method E): [MH]⁺=339/341, t_(R)=3.51 min.

1-(3-(Quinolin-6-ylmethyl)imidazo[1,2-a]pyrimidin-6-yl)ethanone (W)

A solution of 6((6-bromoimidazo[1,2-a]pyrimidin-3-yl)methyl)quinolineand 6-(6-bromo-imidazo[1,2-a]pyrimidin-2-ylmethyl)quinoline (mixture,250 mg, 0.737 mmol), PdCl₂(PPh₃)₂ (51.7 mg, 0.074 mmol) andtributyl(1-ethoxyvinyl)stannane (399 mg, 1.106 mmol) in 5 mL of1,4-dioxane was heated at 80° C. for 12 h under N₂. The reaction mixturewas diluted with EtOAc, washed with water. The organic layer was driedover Na₂SO₄, filtered and concentrated in vacuo. The residue wasdissolved in HOAc and 3 N HCl and stirred at room temperature for 3hours. The solvent was removed under reduced pressure and the residuewas dissolved in CH₂Cl₂, washed with sat. aqueous NaHCO₃ and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by flash chromatography in silica gel elutingwith a EtOAc/MeOH gradient to afford the title compound as a yellowsolid. ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.97 (d, 1H), 8.84 (d, 1H), 8.67(d, 1H), 8.04-7.99 (m, 2H), 7.74 (s, 1H), 7.53-7.51 (m, 1H), 7.34 (dd,1H), 7.19 (s, 1H), 4.44 (s, 2H), 2.49 (s, 3H).

Example 1(E)-1-(3-((7-Fluoroquinolin-6-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanoneO-ethyl oxime

6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-(7-fluoro-quinolin-6-yl)-methanol(1.1)

To a solution of 3-bromo-6-chloro-imidazo[1,2-b]pyridazine (13.27 g,57.1 mmol) in 160 mL THF was added EtMgBr (1M in THF, 68.5 mL, 68.5mmol) solution at rt. The reaction mixture was stirred for 30 min and asuspension of 7-fluoro-quinoline-6-carbaldehyde (10 g, 57.1 mmol) in 40mL of THF was added. The resulting mixture was stirred at it for 3 h andthen quenched with 400 mL water and stirred for an additional 1 h. Theprecipitate was collected by filtration, washed with EtOAc and driedover vacuum oven overnight to afford 13 g (69%) of the title compound.¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.91 (dd, 1H), 8.49 (d, 1H), 8.28 (d,1H), 8.24 (d, 1H), 7.74 (d, 1H), 7.54 (q, 1H), 7.51 (s, 1H), 7.40 (d,1H), 6.54 (m, 2H).

6-(6-Chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (1.2)

To a solution of6-chloro-imidazo[1,2-b]pyridazin-3-yl)-(7-fluoro-quinolin-6-yl)-methanol(9.48 g, 28.8 mmol) in acetic acid (80 mL) was added phosphinic acid(50% aqueous solution, 15.73 mL, 144 mmol) and iodine (18.3 g, 72.1mmol). The resulting solution was heated at 110° C. overnight. Thesolvent was removed under reduced pressure. The residue was diluted withwater and pH of the mixture was adjusted to 8-10 with 6N NaOH solution.The mixture then was extracted with DCM. The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by column chromatography (5% to 10% MeOHin DCM) to afford 5.8 g (64.3%) of the title compound. ¹H-NMR (400 MHz,CDCl₃) δ ppm 8.91 (dd, 1H), 8.14 (d, 1H), 7.93 (d, 1H), 7.85 (d, 1H),7.75 (d, 1H), 7.66 (s, 1H), 7.41 (q, 1H), 7.09 (d, 1H), 4.56 (s, 2H).LCMS (method B): [MH]⁺=313, t_(R)=2.48 min.

1-[3-(7-Fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone(1.3)

To a flask loaded with tetrakis-(triphenylphosphine)-palladium (1.7 g,1.48 mmol) under nitrogen was added a solution of6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (5.8g, 18.55 mmol) in DMF (150 mL). The system was purged with nitrogenthree times and then tributyl-(1-ethoxy-vinyl)-stannane (6.59 mL, 19.47mmol) was added. The temperature was increased to 100° C. and stirredovernight. After cooling, 20 mL of 3N HCl was added and the mixture wasstirred for additional 2 h. Water was added and the product was thenextracted with EtOAc. The combined organic layers were dried over Na₂SO₄and concentrated under reduced pressure. The residue was purified bycolumn chromatography to afford 4.8 g (79%) of the title compound as adark yellow solid. ¹H-NMR (400 MHz, MeOH-d₄) δ ppm 8.82 (dd, 1H), 8.31(d, 1H), 8.10 (d, 1H), 7.98 (d, 1H), 7.85 (s, 1H), 7.78 (d, 1H), 7.72(d, 1H), 7.50 (q, 1H), 4.72 (s, 2H), 2.68 (S, 3H). LCMS (method A):[MH]⁺=321, t_(R)=5.07 min.

(E)-1-(34(7-fluoroquinolin-6-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanoneO-ethyl oxime (Example 1)

To a solution of1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone(50 mg, 0.16 mmol) in methanol (10 mL) was added O-ethylhydroxylaminehydrochloride (46 mg, 0.47 mmol). Triethyl amine was added dropwise toadjust the pH to 5-6. The reaction mixture was stirred at rt overnight.The solution was concentrated under reduced pressure and the residue waspurified by prep-HPLC to afford 30 mg (53%) of the title compound as awhite solid. ¹H-NMR (400 MHz, MeOH-d₄) 3 ppm 8.82 (dd, 1H), 8.30 (d,1H), 7.93 (m, 2H), 7.85 (d, 1H), 7.70 (d, 1H), 7.66 (s, 1H), 7.49 (q,1H), 4.62 (s, 2H), 4.31 (q, 2H), 2.27 (s, 3H), 1.36 (t, 3H). LCMS(method C): [MH]⁺=364, t_(R)=4.71 min.

Example 2(E)-1-(3-((7-Fluoroquinolin-6-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanoneO-methyl oxime

The title compound was prepared in analogy to the synthesis ofexample 1. ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.88 (d, 1H), 8.03 (d, 1H),7.87 (d, 1H), 7.76 (m, 2H), 7.68 (d, 1H), 7.67 (s, 1H), 7.35 (q, 1H),4.58 (s, 2H), 4.06 (s, 3H), 2.31 (s, 3H). LCMS (method C): [MH]⁺=350,t_(R)=4.40 min.

Example 3(E)-1-(3-((7-Fluoroquinolin-6-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime

The title compound was prepared in analogy to the synthesis ofexample 1. ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.88 (d, 1H), 8.03 (d, 1H),7.88 (d, 1H), 7.77 (d, 1H), 7.69 (m, 3H), 7.35 (q, 1H), 4.58 (s, 2H),4.39 (t, 2H), 3.96 (m, 2H), 2.36 (s, 3H). LCMS (method A): [MH]⁺=380,t_(R)=5.15 min.

Example 4(E)-1-(3-(Quinolin-6-ylmethyl)imidazo[1,2-b]pyridazin-6-yl)ethanoneO-ethyl oxime

The title compound was prepared in analogy to the synthesis ofexample 1. ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.86 (dd, 1H), 8.04 (m, 2H),7.82 (d, 1H), 7.70 (m, 3H), 7.59 (s, 1H), 7.35 (q, 1H), 4.51 (s, 2H),4.28 (q, 2H), 2.28 (s, 3H), 1.35 (t, 3H). LCMS (method C): [MH]⁺=346,t_(R)=4.54 min.

Example 5(E)-1-(3-(Quinolin-6-ylmethyl)imidazo[1,2-b]pyridazin-6-yl)ethanoneO-methyl oxime

The title compound was prepared in analogy to the synthesis ofexample 1. ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.86 (dd, 1H), 8.04 (m, 2H),7.83 (d, 1H), 7.71 (m, 3H), 7.60 (s, 1H), 7.35 (q, 1H), 4.51 (s, 2H),4.04 (s, 3H), 2.28 (s, 3H). LCMS (method C): [MH]⁺=332, t_(R)=3.96 min.

Example 6(E)-1-(3-(Quinolin-6-ylmethyl)imidazo[1,2-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime

The title compound was prepared in analogy to the synthesis ofexample 1. ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.87 (dd, 1H), 8.06 (m, 2H),7.85 (d, 1H), 7.69 (m, 4H), 7.37 (q, 1H), 4.52 (s, 2H), 4.38 (m, 2H),3.97 (t, 2H), 2.31 (s, 3H). LCMS (method A): [MH]⁺=362, t_(R)=4.80 min.

Example 7A and 7B(E)-1-(3-(Quinolin-6-ylmethyl)imidazo[1,2-b]pyridazin-6-yl)ethanoneO-1,3-dihydroxypropan-2-yl oxime and(E)-1-(3-(quinolin-6-ylmethyl)imidazo[1,2-b]pyridazin-6-yl)ethanoneO-2,3-dihydroxypropyl oxime

To a mixture of 2-(2,3-dihydroxypropoxy)isoindoline-1,3-dione and2-(1,3-dihydroxypropan-2-yloxy)isoindoline-1,3-dione (1:1 mixture)(intermediate B) in MeOH was added hydrazine monohydrate. The reactionmixture was allowed to stir at reflux for two h and then the solvent wasremoved under reduced pressure. The residue was washed with EtOAc andfiltered. The filtrate was collected, evaporated and redissolved inMeOH. Then1-(3-(quinolin-6-ylmethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone(prepared in analog of compound 1.3) was added and the reaction mixturewas allowed to stir at 30° C. for 5 h. After purifying by HPLC the titlecompounds were separated and obtained as a white solid. Data for example7A: ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.85 (d, 1H), 8.05 (m, 2H), 7.82 (d,1H), 7.65 (m, 4H), 7.36 (q, 1H), 4.49 (m, 3H), 3.98 (d, 4H), 2.26 (s,3H). LCMS (method A): [MH]⁺=392, t_(R)=3.98 min. Data for example 7B:¹H-NMR (400 MHz, CDCl₃) δ ppm 8.89 (dd, 1H), 8.08 (m, 2H), 7.88 (d, 1H),7.69 (m, 4H), 7.39 (q, 1H), 4.55 (s, 2H), 4.36 (d, 2H), 4.13 (m, 1H),3.81 (dd, 1H), 3.69 (dd, 1H), 2.34 (s, 3H). LCMS (method A): [MH]⁺=392,t_(R)=4.42 min.

Example 8(E)-1-(3-((5,7-Difluoroquinolin-6-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanoneO-methyl oxime

The title compound was prepared in analogy to the synthesis ofexample 1. ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.96 (dd, 1H), 8.47 (d, 1H),8.05 (d, 1H), 7.68 (m, 2H), 7.59 (m, 2H), 4.58 (s, 2H), 3.99 (s, 3H),2.23 (s, 3H). LCMS (method A): [MH]⁺=368, t_(R)=5.58 min.

Example 9(E)-1-(3-((5,7-Difluoroquinolin-6-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime

The title compound was prepared in analogy to the synthesis of compoundof example 1. ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.96 (dd, 1H), 8.47 (d, 1H),8.04 (d, 1H), 7.69 (m, 4H), 4.58 (s, 2H), 4.22 (t, 2H), 3.67 (t, 2H),2.24 (s, 3H). LCMS (method A): [MH]⁺=398, t_(R)=5.52 min.

Example 10(E)-1-(3-((5,7-Difluoroquinolin-6-yl)(hydroxy)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanoneO-methyl oxime

(6-Chloroimidazo[1,2-b]pyridazin-3-yl)(5,7-difluoroquinolin-6-yl)methanol(10.1)

To a solution of 3-bromo-6-chloro-imidazo[1,2-b]pyridazine (2.40 g,10.35 mmol) in 30 mL of THF was added EtMgBr (1M in THF, 12.43 mL, 12.42mmol) solution at rt. The solution was stirred for 30 min and a solutionof 5,7-difluoroquinoline-6-carbaldehyde (2.0 g, 10.35 mmol) in 10 mL ofTHF was added. The resulting mixture was stirred at rt for additional 2h and then quenched with 50 mL of NH₄Cl solution. The solution wasextracted with EtOAc and the combined organic layers were washed withwater, brine, dried over Na₂SO₄ and concentrated in vacuo to afford 3.48g (97%) of the title compound. LCMS (method B): [MH]⁺=347, t_(R)=1.23min.

1-(3-((5,7-Difluoroquinolin-6-yl)(hydroxy)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanone(10.2)

To a flask charged with Pd(PPh₃)₄ (67 mg, 0.058 mmol) under nitrogen wasadded a solution of(6-chloroimidazo[1,2-b]pyridazin-3-yl)(5,7-difluoroquinolin-6-yl)methanol(200 mg, 0.56 mmol) in DMF (10 mL). The system was purged with nitrogengas three times and then tributyl-(1-ethoxy-vinyl)-stannane (0.21 mL,0.61 mmol) was added. The temperature was increased to 100° C. andstirred overnight. Then the reaction mixture was cooled to rt, 3N HClwas added and the mixture was stirred for additional 4 h. Water wasadded and the product was extracted with EtOAc. The organic layers werecombined, dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography (3% to 10% MeOH in DCM) toafford 132 mg (55%) of the title compound. ¹H-NMR (400 MHz, CDCl₃). ppm8.98 (dd, 1H), 8.42 (d, 1H), 8.05 (dd, 1H), 8.00 (s, 1H), 7.77 (dd, 1H),7.68 (d, 1H), 7.48 (q, 1H), 7.03 (s, 1H), 2.72 (s, 3H). LCMS (method B):[MH]⁺=355, t_(R)=2.08 min.

(E)-1-(3-((5,7-Difluoroquinolin-6-yl)(hydroxy)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanoneO-methyl oxime (Example 10)

The title compound was prepared in analogy to the synthesis ofexample 1. ¹H-NMR (400 MHz, MeOH-d₄) ppm 8.89 (d, 1H), 8.52 (d, 1H),7.90 (m, 2H), 7.65 (m, 3H), 6.89 (s, 1H), 3.98 (s, 3H), 2.09 (s, 3H).LCMS (method A): [MH]⁺=384, t_(R)=5.34 min.

Example 11 Example 11-R, Example 11-S(E)-1-(3-(1-(7-Fluoroquinolin-6-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime

(6-Chloroimidazo[1,2-b]pyridazin-3-yl)(7-fluoroquinolin-6-yl)methanone(11.1)

To a suspension of(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-(7-fluoro-quinolin-6-yl)-methanol(1.8 g, 5.48 mmol) in acetone (200 mL) was added IBX (8.52 g, 45%, 13.69mmol). The reaction mixture was stirred at reflux for 1 day. Then thesolvent was removed under reduced pressure and the residue was dissolvedin 200 mL of water. The solution was basified by 3N NaOH solution andthe precipitate was collected, washed with water and dried over vacuumoven to afford 1.7 g (95%) of the title compound as a gray solid. ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 9.04 (dd, 1H), 8.56 (d, 1H), 8.47 (m, 2H), 8.41(s, 1H), 7.92 (d, 1H), 7.75 (d, 1H), 7.64 (q, 1H). LCMS (method B):[MH]⁺=327, t_(R)=2.03 min.

1-(6-Chloroimidazo[1,2-b]pyridazin-3-yl)-1-(7-fluoroquinolin-6-yl)ethanol(11.2)

To a solution of(6-chloroimidazo[1,2-b]pyridazin-3-yl)(7-fluoroquinolin-6-yl)methanone(2.93 g, 6.73 mmol) in THF (80 mL) was added MeMgI solution (3 M in THF,4.48 mL, 13.45 mmol) and the resulting solution was stirred at refluxfor 5 h. Then the reaction mixture was cooled to rt, quenched withwater, washed with NH₄Cl solution and extracted by DCM. The combinedorganic layers were dried over Na₂SO₄ and concentrated under reducedpressure to afford 2.2 g (95%) of the title compound which was used tonext step.

6-(1-(6-Chloroimidazo[1,2-b]pyridazin-3-yl)ethyl)-7-fluoroquinoline(11.3)

To a solution of1-(6-chloroimidazo[1,2-b]pyridazin-3-yl)-1-(7-fluoroquinolin-6-yl)ethanol(420 mg, 1.10 mmol) in acetic acid (20 mL) was added phosphinic acid(50% aqueous solution, 0.60 mL, 5.51 mmol) and iodine (700 mg, 2.76mmol). The resulting solution was heated at 110° C. overnight. Solventswas then removed. The residue was diluted with water and pH was adjustedto 8-10 with 6N NaOH solution. The product was extracted by DCM and thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by columnchromatography (3% to 10% MeOH in DCM) to afford 260 mg (72%) of thetitle compound. LCMS (method B): [MH]⁺=327, t_(R)=2.52 min.

1-(3-(1-(7-Fluoroquinolin-6-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone(11.4)

To a flask charged with Pd(PPh₃)₄ (46 mg, 0.040 mmol) under nitrogen wasadded a solution of6-(1-(6-chloroimidazo[1,2-b]pyridazin-3-yl)ethyl)-7-fluoroquinoline (130mg, 0.40 mmol) in DMF (5 mL). The system was purged with nitrogen gasthree times and then tributyl-(1-ethoxy-vinyl)-stannane (0.14 mL, 0.42mmol) was added. The temperature was increased to 100° C. and stirredfor 2 h. Then the reaction mixture was cooled to rt, 3N HCl was addedand the mixture was stirred for additional 4 h. Water was added and theproduct was then extracted with EtOAc. The organic layers were combined,dried over Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography (3% to 10% MeOH in DCM) to afford120 mg (90%) of the title compound. LCMS (method B): [MH]⁺=335,t_(R)=2.41 min.

(E)-1-(3-[1-(7-Fluoroquinolin-6-yl)ethyl]imidazo[1,2-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime (Example 11, Example 11-R, Example 11-S)

The title compound was prepared in analogy to the synthesis ofexample 1. ¹H-NMR (400 MHz, MeOH-d₄) δ ppm 8.79 (d, 1H), 8.22 (d, 1H),7.89 (dd, 1H), 7.80 (s, 1H), 7.74 (m, 3H), 7.44 (q, 1H), 5.12 (q, 1H),4.28 (t, 2H), 3.80 (t, 2H), 2.12 (s, 3H), 1.91 (d, 3H). LCMS (method A):[MH]⁺=394, t_(R)=5.37 min. Chiral separation (method F) providedenantiomeric pure compounds example 11-R and example 11-S.

Example 12 Example 12-R, Example 12-S(E)-1-(3-(1-(5,7-Difluoroquinolin-6-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime

The title compounds as a racemic mixture were prepared in analogy to thesynthesis of example 11. ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.90 (dd, 1H),8.32 (d, 1H), 7.87 (s, 1H), 7.84 (d, 1H), 7.61 (d, 1H), 7.55 (d, 1H),7.40 (q, 1H), 5.23 (q, 1H), 4.34 (m, 2H), 3.93 (m, 2H), 2.19 (s, 3H),2.01 (d, 3H). LCMS (method A): [MH]⁺=412, t_(R)=5.77 min. Chiralseparation (method G) provided enantiomeric pure compounds example 12-Rand 12-S.

Example 13(E)-1-[3-(1-Methyl-1H-indazol-5-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanoneO-(2-hydroxy-ethyl)-oxime

(6-Chloroimidazo[1,2-b]pyridazin-3-yl)(1-methyl-1H-indazol-5-yl)methanol(13.1)

To a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (232.0 mg,1.00 mmol) in THF (5 mL) was added EtMaBr (1M in THF, 1.50 mL, 1.50mmol) at −10° C. After stirring at −10° C. for 1 h,1-methyl-1H-indazole-5-carbaldehyde (240.0 mg, 1.50 mmol) was added. Themixture was allowed to warm to it slowly and stirred for 2 h. Thereaction was quenched with saturated NH₄Cl solution and concentratedunder reduced pressure. The residue was diluted with water and extractedwith EtOAc twice. The organic layers were combined, dried over Na₂SO₄and concentrated. The crude product was washed with DCM to give thetitle compound as a white solid (230 mg, 70%). ¹H-NMR (400 MHz, DMSO-d₆)δ ppm 8.21 (d, 1H), 8.02 (s, 1H), 7.81 (s, 1H), 7.59 (d, 1H), 7.56 (s,1H), 7.49 (d, 1H), 7.35 (d, 1H), 6.29 (d, 1H), 6.21 (d, 1H), 4.02 (s,3H). LCMS (method A): [MH]⁺=314, t_(R)=4.44 min.

6-Chloro-3-((1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine(13.2)

A solution of(6-chloroimidazo[1,2-b]pyridazin-3-yl)(1-methyl-1H-indazol-5-yl)methanol(156.8 mg, 0.50 mmol), I₂ (381 mg, 1.50 mmol) and H₃PO₂ (0.273 mL, 2.50mmol) in AcOH (4 mL) was heated at 110° C. for 7 h. The solvent wasremoved under reduced pressure. The residue was diluted with water andextracted with DCM twice. The organic layers were combined, dried overNa₂SO₄ and concentrated. The crude product was purified by flashchromatography (DCM:MeOH=20:1) to give the title compound containingsome iodine and used in the next step without further purification(180.0 mg, 36% purity, 44%). LCMS (method A): [MH]⁺=298, t_(R)=5.37 min.

6-(1-Ethoxy-vinyl)-3-(1-methyl-1H-indazol-5-ylmethyl)-imidazo[1,2-b]pyridazine(13.3)

A suspension of6-chloro-3-((1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine(180.0 mg, 36% purity, 0.22 mmol), tributyl(1-ethoxyvinyl)stannane (94mg, 0.26 mmol) and Pd(PPh₃)₄ (25.1 mg, 0.02 mmol) in 10 mL of DMF wasflushed with nitrogen, then heated at 110° C. and stirred overnight.Solvent was removed under reduced pressure; the residue was diluted withDCM, washed sequentially with aqueous KF and water. The organic layerwas dried over Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified by flash chromatography (DCM:MeOH=20:1) to give thetitle compound containing some triphenylphosphine oxide impurity butused in the next step without further purification (49 mg, 47%, 70%purity). LCMS (method A): [MH]⁺=334, t_(R)=5.71 min.

1-(3-((1-Methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanone(13.4)

A solution of6-(1-ethoxy-vinyl)-3-(1-methyl-1H-indazol-5-ylmethyl)-imidazo[1,2-b]pyridazine(50 mg, 0.15 mmol) and HCl (0.15 mL, 0.15 mmol) in AcOH (10 mL) washeated at 50° C. for 3 h. The solvent was removed under reducedpressure. The residue was diluted with water and pH of solution wasadjusted to around 8 with saturated NaHCO₃ solution, then was extractedwith DCM three times. Organic layers were combined, dried over Na₂SO₄and concentrated. The crude product was used in the next step withoutpurification (45 mg, 75%, 76% purity). LCMS (method A): [MH]⁺=306,t_(R)=5.03 min.

(E)-1-[3-(1-Methyl-1H-indazol-5-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanoneO-(2-hydroxy-ethyl)-oxime (Example 13)

A solution of1-(3-((1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanone(20.0 mg, 0.07 mmol) and 2-(aminooxy)ethanol hydrochloride (14.87 mg,0.13 mmol) in 10 mL THF was stirred at 40° C. overnight. Solvent wasremoved in vacuo. The crude product was purified on flash chromatography(DCM:MeOH=50:1) to give the title compound as a yellow solid (15.0 mg,57%). ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.04 (d, 1H), 7.94 (s, 1H),7.68˜7.61 (m, 3H), 7.54 (d, 1H), 7.39 (d, 1H), 4.41 (s, 2H), 4.23 (s,2H), 3.98 (s, 3H), 3.68 (s, 2H), 2.29 (s, 3H). LCMS (method A):[MH]⁺=365, t_(R)=4.70 min.

Example 14(E)-1-{3-[1-(1-Methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazin-6-yl}-ethanoneO-(2-hydroxy-ethyl)-oxime

(6-Chloroimidazo[1,2-b]pyridazin-3-yl)(1-methyl-1H-indazol-5-yl)methanone(14.1)

A suspension of(6-chloroimidazo[1,2-b]pyridazin-3-yl)(1-methyl-1H-indazol-5-yl)methanol(13.1) (500.0 mg, 1.60 mmol) and 2-Iodoxybenzoic acid (45%)(1488.0 mg,2.39 mmol) in 10 mL acetone was heated at reflux for 3 h. Solvent wasremoved under reduced pressure. The residue was diluted with water; pHwas adjusted to around 10 with 10% NaOH aqueous solution. Theprecipitates were collected by filtration and washed with water threetimes. The solid was dissolved in DCM, dried over Na₂SO₄, filtered andconcentrated to give the title compound as a white solid (410.0 mg,78%). ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.46 (s, 1H), 8.42 (m, 1H), 8.32(m, 1H), 8.27 (d, 1H), 7.95 (dd, 1H), 7.815 (d, 1H), 7.66 (d, 1H), 4.12(s, 2H). LCMS (method A): [MH]⁺=312, t_(R)=4.64 min.

1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(1-methyl-1H-indazol-5-yl)-ethanol(14.2)

To a solution of(6-chloroimidazo[1,2-b]pyridazin-3-yl)(1-methyl-1H-indazol-5-yl)methanone(410 mg, 1.32 mmol) in 10 mL THF was added methylmagnesium iodide (0.88mL, 2.63 mmol) at 0° C. After stirring at 0° C. for 3 h, the reactionwas quenched with saturated NH₄Cl and concentrated under resduepressure. The residue was extracted with DCM three times. The organiclayers were combined, dried over Na₂SO₄ and concentrated to give thetitle compound as a white solid (430.0 mg, 95%). ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.17 (d, 1H), 7.99 (s, 1H), 7.50 (m, 1H), 7.40 (d, 1H),7.25 (d, 1H), 5.98 (s, 1H), 3.99 (s, 3H), 2.05 (s, 3H). LCMS (method A):[MH]⁺=328, t_(R)=4.55 min.

6-Chloro-3-[1-(1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine(14.3)

The title compound (390.0 mg, 91%) was synthesized from1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(1-methyl-1H-indazol-5-yl)-ethanol(430.0 mg, 1.31 mmol), I₂ (832.0 mg, 3.28 mmol) and H₃PO₂(0.72 mL, 6.56mmol) using the same procedure as described in the synthesis of compound13.2. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.18 (d, 1H), 7.95 (s, 1H), 7.83(s, 1H), 7.55 (m, 2H), 7.36 (d, 1H), 7.28 (d, 1H), 4.70 (q, 1H), 3.99(s, 3H), 1.74 (d, 3H). LCMS (method A): [MH]⁺=312, t_(R)=5.49 min.

6-(1-Ethoxy-vinyl)-3-[1-(1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine(14.4)

The title compound (415.0 mg, 86%, 90% purity) was synthesized from6-chloro-3-[1-(1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine(390.0 mg, 1.25 mmol), tributyl(1-ethoxyvinyl)stannane (497.0 mg, 1.38mmol) and Pd(PPh₃)₄ (145 mg, 0.13 mmol) using the same procedure asdescribed in the synthesis of compound 13.3. LCMS (method A): [MH]⁺=348,t_(R)=5.86 min.

1-(3-(1-(1-Methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone(14.5)

The title compound (325.0 mg, 75%, 88% purity) was synthesized from6-(1-ethoxy-vinyl)-3-[1-(1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine(415.0 mg, 1.20 mmol) and HCl (1.20 mL, 1.20 mmol) using the sameprocedure as described in the synthesis of compound 13.4. LCMS (methodA): [MH]⁺=320, t_(R)=5.21 min.

(E)-1-{3-[1-(1-Methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazin-6-yl}-ethanoneO-(2-hydroxy-ethyl)-oxime (Example 14)

The title compound (9.0 mg, 17%, 88% purity) was synthesized from1-(3-(1-(1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone(40.0 mg, 0.13 mmol) and 2-(aminooxy)ethanol hydrochloride (19.31 mg,0.25 mmol) using the same procedure as described in the synthesis ofexample 13. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 7.94 (d, 1H), 7.85 (s, 1H),7.79 (s, 1H), 7.66 (s, 1H), 7.85 (d, 1H), 7.52 (d, 1H), 7.37 (dd, 1H),4.72 (t, 2H), 4.21 (t, 2H), 3.97 (s, 3H), 3.66 (q, 1H), 2.20 (s, 3H),1.78 (d, 3H). LCMS (method A): [MH]⁺=379, t_(R)=5.25 min.

Example 15(E)-1-[3-(7-Fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanoneO-(2-hydroxy-ethyl)-oxime

5-Bromo-N*3*-(7-fluoro-quinolin-6-ylmethyl)-pyrazine-2,3-diamine (15.1)

A mixture of C-(7-fluoro-quinolin-6-yl)-methylamine (1.69 g, 9.63 mmol),3,5-dibromopyrazin-2-amine (2.43 g, 9.63 mmol) and DIPEA (2.96 g, 22.90mmol) was heated with microwave irradiation at 120° C. for 10 h. Thereaction mixture was diluted with DCM and water. The organic layer wasseparated and washed with saturated NH₄Cl solution, dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product was purified bysilica gel chromatography (DCM:MeOH) to give the title compound as ayellow solid (2.60 g, 69%). LCMS (method E): [MH]⁺=348/350, t_(R)=5.21min.

6-(6-Bromo-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl)-7-fluoro-quinoline(15.2)

To a solution of5-bromo-N*3*-(7-fluoro-quinolin-6-ylmethyl)-pyrazine-2,3-diamine (90 mg,0.26 mmol) in acetic acid (4 mL) was added a solution of sodium nitrite(11.4 mg, 0.26 mmol) in water (1 mL). After stirring at rt for 3 h, thesolvent was removed in vacuo. The residue was diluted with NaHCO₃ (aq.),extracted with DCM. The organic layer was separated and washed withwater, dried over Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified by silica gel chromatography with DCM:MeOH=50:1 togive the title compound as a yellow solid (57.0 mg, 61%). ¹H-NMR (400MHz, DMSO-d₆) δ ppm 9.03 (s, 1H), 8.94 (d, 1H), 8.40 (d, 1H), 8.08 (d,1H), 7.84 (d, 1H), 7.55 (dd, 1H), 7.53 (dd, 1H), 6.21 (s, 2H). LCMS(method A): [MH]⁺=359/361, t_(R)=2.23 min.

6-[6-(1-Ethoxy-vinyl)-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl]-7-fluoro-quinoline(15.3)

A mixture of6-(6-bromo-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl)-7-fluoro-quinoline(2.0 g, 5.57 mmol), Pd(Ph₃P)₄ (0.64 g, 0.56 mmol) andtributyl(1-ethoxyvinyl)stannane (4.02 g, 11.14 mmol) in DMF (50 mL) waspurged with nitrogen and then heated at 100° C. for 7 h. After removalof the solvent under reduced pressure, the residue was diluted with DCM,washed sequentially with aqueous KF and water, dried over Na₂SO₄ andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel with gradient (DCM:MeOH=50:1) to give thetitle compound as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.11(s, 1H), 8.93 (d, 1H), 8.40 (d, 1H), 8.15 (d, 1H), 7.83 (d, 1H), 7.54(m, 1H), 6.22 (s, 2H), 5.50 (d, 1H), 4.73 (d, 1H), 4.02 (q, 2H), 1.40(t, 3H). LCMS (method E): [MH]⁺=351, t_(R)=5.42 min.

1-[3-(7-Fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone(15.4)

A solution of6-[6-(1-ethoxy-vinyl)-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl]-7-fluoro-quinoline(600.0 mg, 0.89 mmol) and 3 N HCl (0.1 mL) in acetic acid was stirred at50° C. for 2 h. The solvent was removed under reduced pressure. Theresidue was diluted with water; the pH of solution was adjusted toaround 8 with aqueous NaHCO₃; extracted with DCM twice. The combinedorganic layers were washed sequentially with water and brine, dried overNa₂SO₄, filtered and concentrated in vacuo to give the title compound aswhite solid (630 mg, 96%). ¹H-NMR (400 MHz, CDCl₃) δ ppm 9.46 (s, 1H),8.94 (d, 1H), 8.11 (d, 2H), 7.85 (dd, 1H), 7.41 (dd, 1H), 6.23 (s, 2H),2.79 (s, 3H). LCMS (method A): [MH]⁺=323, t_(R)=2.23 min.

1-[3-(7-Fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanoneO-(2-hydroxy-ethyl)-oxime (Example 15)

To a solution of1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone(190.0 mg, 0.59 mmol) in MeOH (40 mL) was added 2-(aminooxy)ethanolhydrochloride (134.0 mg, 1.18 mol). The mixture was heated at 45° C.overnight. The solvent was removed under reduced pressure. The residuewas purified by column chromatography with gradient (DCM:MeOH=10:1) togive the title compound as a white solid (168.0 mg, 71%). ¹H-NMR (400MHz, DMSO-d₆) δ ppm 9.30 (s, 1H), 8.93 (d, 1H), 8.41 (d, 1H), 8.19 (d,1H), 7.83 (d, 1H), 7.54 (dd, 1H), 6.24 (s, 2H), 4.78 (t, 1H), 4.31 (t,2H), 3.72 (m, 2H), 2.29 (s, 3H). LCMS (method A): [MH]⁺=382, t_(R)=4.99min.

Example 16(E)-1-[3-(7-Fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanoneO-methyl-oxime

The title compound (22.2 mg, 64%) was synthesized from1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone(15.4) (30.0 mg, 0.09 mmol) and O-methyl-hydroxylamine hydrochloride(78.0 mg, 0.93 mmol) using the same procedure as described in thesynthesis of example 15. ¹H-NMR (400 MHz, CDCl₃) δ ppm 9.45 (s, 1H),8.92 (d, 1H), 8.08 (d, 1H), 7.81 (d, 1H), 7.78 (s, 1H), 7.39 (dd, 1H),6.16 (s, 2H), 4.13 (s, 3H), 2.33 (s, 3H). LCMS (method E): [MH]⁺=352,t_(R)=5.43 min.

Example 17(E)-1-[3-(7-Fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanoneO-(2-hydroxy-1,1-dimethyl-ethyl)-oxime

The title compound (12.0 mg, 89%) was synthesized from1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone(15.4) (10.0 mg, 0.03 mmol) and 2-aminooxy-2-methyl-propan-1-olhydrochloride (8.8 mg, 0.06 mmol) using the same procedure as describedin the synthesis of example 15. ¹H-NMR (400 MHz, CDCl₃) δ ppm 9.41 (s,1H), 8.94 (d, 1H), 8.18 (d, 1H), 7.94 (d, 1H), 7.83 (s, 1H), 7.46 (dd,1H), 6.17 (s, 2H), 3.75 (d, 2H), 2.36 (s, 3H), 1.95 (1, 1H), 1.41 (s,6H). LCMS (method A): [MH]⁺=410, t_(R)=5.39 min.

Example 18(E)-1-[3-(7-Fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanoneO-(2-hydroxy-2-methyl-propyl)-oxime

The title compound (12.0 mg, 89%) was synthesized from1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone(15.4) (10.0 mg, 0.03 mmol) and 1-aminooxy-2-methyl-propan-2-ol (6.5 mg,0.06 mmol) using the same procedure as described in the synthesis ofexample 15. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.29 (s, 1H), 8.93 (dd, 1H),8.41 (dd, 1H), 8.19 (d, 1H), 7.83 (d, 1H), 7.54 (dd, 1H), 6.23 (s, 2H),4.60 (s, 1H), 4.12 (d, 2H), 2.30 (s, 3H), 1.17 (s, 6H). LCMS (method A):[MH]⁺=410, t_(R)=5.40 min.

Example 19(S,E)-1-(1-((7-Fluoroquinolin-6-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-pyrrolidin-3-yl oxime

The title compound (37.0 mg, 70%) was synthesized from1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone(15.4) (40.0 mg, 0.12 mmol) and (S)-O-pyrrolidin-3-yl-hydroxylaminehydrochloride (30.0 mg, 0.17 mmol) using the same procedure as describedin the synthesis of example 15. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.30 (s,1H), 8.92 (dd, 1H), 8.41 (dd, 1H), 8.18 (d, 1H), 7.82 (d, 1H), 7.53 (dd,1H), 6.23 (s, 2H), 4.95 (m, 1H), 3.16-2.87 (m, 3H), 2.77-2.71 (m, 1H),2.25 (s, 3H), 2.01-1.87 (m, 2H). LCMS (method A): [MH]⁺=407, t_(R)=3.09min.

Example 20(R,E)-1-(1-((7-Fluoroquinolin-6-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-pyrrolidin-3-yl oxime

The title compound (7.0 mg, 50%) was synthesized from1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone(15.4) (10.0 mg, 0.03 mmol) and (R)-β-pyrrolidin-3-yl-hydroxylaminehydrochloride (10.8 mg, 0.06 mmol) using the same procedure as describedin the synthesis of example 15. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.31 (s,1H), 8.93 (d, 1H), 8.40 (d, 1H), 8.16 (d, 1H), 7.83 (d, 1H), 7.54 (dd,1H), 6.24 (s, 2H), 4.95 (m, 1H), 3.01-2.87 (m, 3H), 2.74-2.67 (m, 1H),2.27 (s, 3H), 2.15-1.90 (m, 2H). LCMS (method A): [MH]⁺=407, t_(R)=3.98min.

Example 21(S,E)-3-(1-(1-((7-Fluoroquinolin-6-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethylideneaminooxy)pyrrolidine-1-carboxamide

To a solution of(S,E)-1-(1-((7-fluoroquinolin-6-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-pyrrolidin-3-yl oxime (example 19) (20.0 mg, 0.05 mmol) in EtOH (5 mL)was added isocyanatotrimethylsilane (7.9 mg, 0.07 mmol). The mixture wasstirred overnight. The solvent was removed under reduced pressure. Theresidue was diluted with MeOH (3 mL) and filtered. The filtrate waspurified on HPLC (basic with 0.05% NH₄OH) to give the title compound asa white solid (15.0 mg, 64%). ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.31 (s,1H), 8.92 (dd, 1H), 8.40 (d, 1H), 8.17 (d, 1H), 7.82 (d, 1H), 7.53 (dd,1H), 6.23 (s, 2H), 5.77 (s, 2H), 4.99 (m, 1H), 3.59 (d, 1H), 3.51-3.47(m, 1H), 3.44-3.38 (m, 1H), 3.28-3.23 (m, 1H), 2.26 (s, 3H), 2.18-2.17(m, 2H). LCMS (method A): [MH]⁺=450, t_(R)=4.38 min.

Example 22(E)-1-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-methyl oxime

6-Bromo-N2-(quinolin-6-ylmethyl)pyrazine-2,3-diamine (22.1)

A mixture of quinolin-6-ylmethanamine (3.6 g, 22.76 mmol),3,5-dibromopyrazin-2-amine (5.75 g, 22.76 mmol) and triethyl amine (4.61g, 45.5 mmol) was heated with microwave irradiation at 130° C. for 5 h.The reaction mixture was diluted with CH₂Cl₂ and water and the organiclayer was separated, washed with aqueous NH₄Cl, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by columnchromatography with EtOAc:hexanes to provide 6.93 g (92%) of the titlecompound. LCMS (method A): [MH]⁺=330, t_(R)=4.89 min.

6-((6-Bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline(22.2)

To a solution of 6-bromo-N2-(quinolin-6-ylmethyl)pyrazine-2,3-diamine(6.55 g, 19.84 mmol) in acetic acid (15 mL) was added a solution ofsodium nitrite (2.74 g, 39.7 mmol) in water (3 mL). After stirring at rtfor 3 h, the solution was concentrated. The residue was taken withNaHCO₃ (aq) and extracted with DCM. The organic layer was washed withNH₄Cl (aq), dried over Na₂SO₄, filtered, concentrated in vacuo andpurified by column chromatography with EtOAc:hexane to provide 3.35 g(47%) of the title compound. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.05 (s,1H), 8.89 (d, 1H), 8.34 (d, 1H), 8.02 (d, 1H), 7.93 (s, 1H), 7.76 (dd,1H), 7.53 (dd, 1H), 6.19 (s, 2H). LCMS (method B): [MH]⁺=343, t_(R)=2.11min.

6-((6-(1-Ethoxyvinyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline(22.3)

To a degassed solution of6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (2.50g, 5.86 mmol) in DMF (20 mL) was added Pd(Ph₃P)₄ (0.542 g, 0.469 mmol).The solution was stirred for 20 min at rt, and thentributyl(1-ethoxyvinyl)stannane (2.117 g, 5.86 mmol) was added. Themixture was heated at 100° C. until LC-MS showed the reaction wascomplete. The reaction mixture was filtered through celite and thefiltrate was washed with water, dried over Na₂SO₄, and concentrated. Theresulting crude product was purified by column chromatography withgradient hexanes:EtOAc to give 1.2 g (62%) of the title compound. ¹H-NMR(400 MHz, CDCl₃) δ ppm 9.19 (s, 1H), 8.94 (m, 1H), 8.20 (m, 1H), 7.99(s, 1H), 7.89 (d, 1H), 7.55 (m, 1H), 6.12 (s, 2H), 5.61 (d, 1H), 4.61(d, 1H), 4.05 (q, 2H), 1.51 (t, 3H). LCMS (method B): [MH]⁺=360,t_(R)=2.40 min.

1-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone(22.4)

To a solution of the6-((6-(1-ethoxyvinyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline(150 mg, 0.451 mmol) in acetic acid was added 3N HCl (0.1 mL). Afterstirring at it for 2 h, solvent was removed under reduced pressure. Theresidue was diluted with water and its pH was adjusted to basic withaqueous NaHCO₃, and extracted with DCM. The combined organic layers werewashed with NaHCO₃ (aq) and brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatographyto give 131 mg (91%) of the title compound as a yellow solid. ¹H-NMR(400 MHz, CDCl₃) δ ppm 9.45 (s, 1H), 8.95 (d, 1H), 8.14 (m, 2H), 7.95(s, 1H), 7.84 (d, 1H), 7.45 (m, 1H), 6.19 (s, 2H), 2.75 (s, 3H). LCMS(method B): [MH]⁺=305, t_(R)=2.95 min.

(E)-1-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-methyl oxime (Example 22)

To a solution of1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone(6.3 mg, 0.021 mmol) in methanol (3 mL) was added O-methylhydroxylaminehydrochloride (16.7 mg, 0.20 mmol), followed by addition of triethylamine to adjust the pH to 5-6. The reaction mixture was stirred at 30°C. for 3 h. The solvent was removed under reduced pressure and theresidue was dissolved in DCM. The resulting solution was washed withNaHCO₃ solution, water and brine, dried over Na₂SO₄ and concentrated invacuo. The crude product was purified by prep-HPLC to afford 5.3 mg(69%) of the title compound. ¹H-NMR (400 MHz, CD₃Cl) δ ppm 9.67 (s, 1H),8.94 (m, 1H), 8.16 (t, 2H), 7.93 (d, 1H), 7.86 (dd, 1H), 7.53 (dd, 1H),6.11 (s, 2H), 4.14 (s, 3H), 2.38 (s, 3H). LCMS (method A): [MH]⁺=334,t_(R)=5.02 min.

Example 23(E)-1-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]-triazolo[4,5-b]pyrazin-6-yl)ethanoneO-2-hydroxyethyl oxime

The title compound was prepared from1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone(22.4) and 2-(aminooxy)ethanol in 21% yield using the same procedure asdescribed in the synthesis of example 22. ¹H-NMR (400 MHz, CD₂Cl₂) δ ppm9.40 (s, 1H), 8.91 (m, 1H), 8.18 (d, 2H), 7.95 (d, 1H), 7.85 (dd, 1H),7.45 (dd, 1H), 6.13 (s, 2H), 4.46 (t, 2H), 3.97 (t, 2H), 2.39 (s, 3H).LCMS (method A): [MH]⁺=364, t_(R)=4.28 min.

Example 241-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneoxime

The title compound was prepared from1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone(22.4) and hydroxylamine hydrochloride in 72% yield using the sameprocedure as described in the synthesis of example 22. ¹H-NMR (400 MHz,DMSO-d₆), δ ppm 9.31 (s, 1H), 8.89 (d, 1H), 8.35 (d, 1H), 8.01 (m, 2H),7.82 (d, 1H), 7.53 (dd, 1H), 6.20 (s, 2H), 2.27 (s, 3H).

Example 25(E)-1-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-ethyl oxime

The title compound was prepared from1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone(22.4) and O-ethylhydroxylamine hydrochloride in 61% yield using thesame procedure as described in the synthesis of example 22. ¹H-NMR (400MHz, DMSO-d₆), δ ppm 9.31 (s, 1H), 8.89 (m, 1H), 8.35 (d, 1H), 8.01 (m,2H), 7.82 (d, 1H), 7.53 (dd, 1H), 6.20 (s, 2H), 4.34 (q, 2H), 2.32 (s,3H), 1.24 (t, 3H). LCMS (method B): [MH]⁺=348, t_(R)=2.59 min.

Example 26A(E)-1-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-1,3-dihydroxypropan-2-yl oxime

The title compound was prepared from1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone(22.4) and 2-(aminooxy)propane-1,3-diol (intermediate B) in 54% yieldusing the same procedure as described in the synthesis of example 22 andexample 7A. ¹H-NMR (400 MHz, CD₃OD), 5 ppm 9.40 (s, 1H), 8.86 (dd, 1H),8.38 (d, 1H), 8.05 (m, 2H), 7.90 (dd, 1H), 7.56 (dd, 1H), 6.22 (s, 2H),4.46 (t, 1H), 3.87 (d, 4H), 2.42 (s, 3H). LCMS (method B): [MH]⁺=394,t_(R)=1.86 min.

Example 26B(E)-1-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-2,3-dihydroxypropyl oxime

The title compound was prepared from1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone(22.4) and (3-(aminooxy)propane-1,2-diol) (intermediate B) in 40% yieldusing the same procedure as described in the synthesis of example 22 andexample 7B. ¹H-NMR (400 MHz, CD₃OD) δ ppm 9.40 (s, 1H), 8.86 (m, 1H),8.38 (d, 1H), 8.05 (m, 2H), 7.90 (dd, 1H), 7.57 (dd, 1H), 6.23 (s, 2H),4.45 (m, 1H), 4.34 (m, 1H), 4.01 (m, 1H), 3.63 (m, 2H), 2.41 (s, 3H).LCMS (method B): [MH]⁺=394, t_(R)=1.96 min.

Example 27(E)-1-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-benzyl oxime

The title compound was prepared from1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone(22.4) and O-benzylhydroxylamine (intermediate H) in 43% yield using thesame procedure as described in the synthesis of example 22 ¹H-NMR (400MHz, CDCl₃), δ ppm 9.43 (s, 1H), 8.93 (d, 1H), 8.13 (m, 2H), 7.91 (s,1H), 7.83 (d, 1H), 7.42 (m, 6H), 6.10 (s, 2H), 5.36 (s, 2H), 2.40 (s,3H). LCMS (method A): [MH]⁺=410, t_(R)=5.94 min.

Example 28(E)-1-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-4-methoxybenzyl oxime

The title compound was prepared from1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone(22.4) and O-(4-methoxybenzyl)hydroxylamine (intermediate G) in 37%yield using the same procedure as described in the synthesis of example22. ¹H-NMR (400 MHz, CDCl₃), δ ppm 9.44 (s, 1H), 8.93 (s, 1H), 8.13 (m,2H), 7.91 (s, 1H), 7.84 (d, 1H), 7.47 (dd, 1H), 7.44 (d, 2H), 6.92 (d,2H), 6.10 (s, 2H), 5.28 (s, 2H), 3.82 (s, 3H), 2.37 (s, 3H). LCMS(method A): [MH]⁺=440, t_(R)=5.94 min.

Example 29(E)-1-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-piperidin-4-yl oxime

To a solution of1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone(22.4) (40 mg, 0.131 mmol) in methanol (10 mL) was added t-butyl4-(aminooxymethyl)piperidine-1-carboxylate (intermediate I) (19.7 mg,0.329 mmol). Acetic acid was added dropwise to adjust the pH to 5-6. Thereaction mixture was stirred at 30° C. for 20 h. The solvent was removedin vacuo and the residue was dissolved in DCM (5 mL), followed byaddition of TFA (0.2 mL). The reaction mixture was stirred at it for 2h, and then concentrated in vacuo to give crude product which waspurified by column chromatography to afford 11 mg (16%) of the titlecompound. ¹H-NMR (400 MHz, CDCl₃), δ ppm 9.45 (s, 1H), 8.93 (m, 1H),8.15 (d, 1H), 8.10 (d, 1H), 7.93 (d, 1H), 7.84 (d, 1H), 7.44 (dd, 1H),6.11 (s, 2H), 4.46 (m, 1H), 3.15 (m, 2H), 2.81 (m, 2H), 2.49 (s, 3H),2.12 (m, 2H), 1.72 (m, 2H). LCMS (method B): [MH]⁺=403, t_(R)=1.59 min.

Example 30(E)-1-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-piperidin-4-ylmethyl oxime

The title compound was prepared from1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone(22.4) and t-butyl 4-(aminooxymethyl)piperidine-1-carboxylate(intermediate J) in 15% yield using the same procedure as described inthe synthesis of example 29. ¹H-NMR (400 MHz, CDCl₃), δ ppm 9.43 (s,1H), 8.93 (m, 1H), 8.13 (m, 2H), 7.92 (s, 1H), 7.83 (dd, 1H), 7.43 (dd,1H), 6.10 (s, 2H), 4.20 (d, 2H), 3.18 (d, 2H), 2.68 (t, 2H), 2.37 (s,3H), 1.98 (br s, 1H), 1.80 (d, 2H), 1.37 (q, 2H). LCMS (method A):[MH]⁺=417, t_(R)=1.66 min.

Example 31 (E)-Methyl2-(1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethylideneaminooxy)acetate

The title compound was prepared from1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone(22.4) and methyl 2-(aminooxy)acetate (intermediate K) in 31% yieldusing the same procedure as described in the synthesis of example 22.¹H-NMR (400 MHz, CD₃OD), δ ppm 9.32 (s, 1H), 8.86 (m, 1H), 8.38 (d, 1H),8.06 (m, 2H), 7.90 (dd, 1H), 7.56 (dd, 1H), 6.24 (s, 2H), 4.87 (s, 2H),3.79 (s, 3H), 2.45 (s, 3H). LCMS (method B): [MH]⁺=392, t_(R)=2.16 min.

Example 32(E)-2-(1-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethylideneaminooxy)acetamide

To a solution of (E)-methyl2-(1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethylideneaminooxy)acetate(example 31) (70 mg, 0.179 mmol) was added ammonia (2 N, 0.268 mL, 0.537mmol). The reaction was heated at reflux for 12 h. The reaction mixturewas concentrated in vacuo to give a crude product which was purified byprep-HPLC to afford 9 mg (16%) of the title compound. ¹H-NMR (400 MHz,DMSO-d₆+D₂O) δ ppm 9.32 (s, 1H), 8.88 (d, 1H), 8.34 (d, 1H), 8.01 (m,2H), 7.81 (d, 1H), 7.52 (dd, 1H), 7.33 (br, 2H), 6.20 (s, 2H), 4.67 (s,2H), 2.27 (s, 3H). LCMS (method B): [MH]⁺=377, t_(R)=1.06 min.

Example 33(E)-1-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-2-hydroxy-2-methylpropyl oxime

The title compound was prepared from1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone(22.4) and 1-(aminooxy)-2-methylpropan-2-ol in 85% yield using the sameprocedure as described in the synthesis of example 22. ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 9.29 (s, 1H), 8.89 (d, 1H), 8.35 (d, 1H), 8.01 (m, 2H),7.82 (dd, 1H), 7.53 (dd, 1H), 6.21 (s, 2H), 4.60 (s, 1H), 4.13 (s, 2H),2.34 (s, 3H), 1.17 (s, 6H). LCMS (method B): [MH]⁺=392, t_(R)=2.38 min.

Example 34(E)-1-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-2-aminoethyl oxime

(E)-2-(2-(1-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethylidene-aminooxy)ethyl)isoindoline-1,3-dione(34.1)

To a solution of(E)-1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-2-hydroxyethyl oxime (example 23) (200 mg, 0.55 mmol) in THF (10 mL)were added triphenylphosphine (144 mg, 0.55 mmol), isoindoline-1,3-dione(81 mg, 0.55 mmol) and (E)-diisopropyl diazene-1,2-dicarboxylate (111mg, 0.55 mmol) sequentially. The mixture was stirred at rt for 48 h andconcentrated in vacuo. The residue was purified by column chromatographyto afford 120 mg (42%) of the title compound. ¹H-NMR (400 MHz, DMSO-d₆)δ ppm 8.90 (s, 1H), 8.89 (m, 1H), 8.35 (d, 1H), 8.02 (m, 2H), 7.81 (d,1H), 7.71 (m, 2H), 7.63 (m, 2H), 7.52 (dd, 1H), 6.19 (s, 2H), 4.53 (t,2H), 3.97 (t, 2H), 2.20 (s, 3H). LCMS (method B): [MH]⁺=493, t_(R)=2.52min.

(E)-1-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-2-aminoethyl oxime (example 34)

To a solution of(E)-2-(2-(1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethylideneaminooxy)ethyl)isoindoline-1,3-dione(70 mg, 0.142 mmol) in MeOH (10 mL) was added hydrazine monohydrate(35.6 mg, 0.711 mmol). The solution was heated at reflux for 30 h andconcentrated in vacuo. The crude was purified by column chromatographyto afford 19 mg (37%) of the title compound. ¹H-NMR (400 MHz,DMSO-d₆+D₂O) δ ppm 9.35 (s, 1H), 8.98 (s, 1H), 8.35 (d, 1H), 8.02 (s,1H), 8.01 (d, 1H), 7.81 (d, 1H), 7.53 (m, 1H), 6.20 (s, 2H), 4.47 (s,2H), 3.22 (s, 2H), 2.34 (s, 3H). LCMS (method B): [MH]⁺=363, t_(R)=1.57min.

Example 35(R,E)-1-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-pyrrolidin-3-yl oxime

The title compound was prepared from1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone(22.4) (25 mg, 0.082 mmol) and (R)-O-(pyrrolidin-3-yl)hydroxylaminedihydrochloride in 60% yield using the same procedure as described inthe synthesis of example 22. ¹H-NMR (400 MHz, CDCl₃) δ ppm 9.41 (s, 1H),8.92 (d, 1H), 8.13 (d, 1H), 8.09 (d, 1H), 7.91 (s, 1H), 7.82 (d, 1H),7.41 (dd, 1H), 6.10 (s, 2H), 5.30 (s, 1H), 5.09 (s, 1H), 3.31 (m, 3H),2.38 (s, 3H), 2.25 (m, 2H). LCMS (method B): [MH]⁺=389, t_(R)=1.17 min.

Example 36(E)-1-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-1-hydroxypropan-2-yl oxime

The title compound was prepared from1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone(22.4) and 2-(aminooxy)propan-1-ol hydrochloride (intermediate Q) in 90%yield using the same procedure as described in the synthesis of example22. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.41 (s, 1H), 8.93 (m, 1H), 8.15 (m,2H), 7.92 (s, 1H), 7.84 (dd, 1H), 7.43 (dd, 1H), 6.12 (s, 2H), 4.61 (m,1H), 3.85 (m, 2H), 2.41 (s, 3H), 2.00 (s, 1H), 1.38 (d, 3H). LCMS(method B): [MH]⁺=378, t_(R)=1.96 min.

Example 37A (E)-Methyl2-(1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethylideneaminooxy)ethylcarbamate

To a solution of(E)-1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-2-aminoethyl oxime (example 34) (6 mg, 0.017 mmol) in DCM (5 mL) wereadded methyl chloroformate (2.66 mg, 0.028 mmol) and triethyl amine(3.35 mg, 0.033 mmol). The mixture was stirred at rt for 10 h. Afterconcentration, the crude was purified by chromatography on silica gel toafford 3.4 mg (46%) of the title compound. ¹H-NMR (400 MHz, CDCl₃) δ ppm9.41 (s, 1H), 8.93 (s, 1H), 8.14 (dd, 2H), 7.92 (s, 1H), 7.84 (dd, 1H),7.44 (m, 1H), 6.12 (s, 2H), 4.42 (t, 2H), 3.69 (s, 3H), 3.60 (m, 2H),2.39 (s, 3H). LCMS (method B): [MH]⁺=421, t_(R)=1.95 min.

Example 37B(E)-1-(2-(1-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethylideneaminooxy)ethyl)urea

To a solution of(E)-1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-2-aminoethyl oxime (example 34) (15 mg, 0.041 mmol) in DCM (5 mL) wasadded trimethylsilyl isocyanate (19.07 mg, 0.166 mmol). The mixture wasstirred for 24 h. After concentration, the crude product was purified bychromatography on silica gel to afford 11.6 mg (69%) of the titlecompound. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.32 (s, 1H), 8.89 (dd, 1H),8.35 (d, 1H), 8.01 (m, 2H), 7.82 (d, 1H), 7.53 (dd, 1H), 6.21 (s, 2H),6.05 (t, 1H), 5.50 (s, 2H), 4.27 (t, 2H), 3.35 (m, 2H), 2.32 (s, 3H).LCMS (method B): [MH]⁺=406, t_(R)=1.91 min.

Example 38(E)-1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine-6-carbaldehydeO-2-hydroxyethyl oxime

6-((6-Vinyl-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline(38.1)

To a degassed solution6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline

(22.2) (1.2 g, 3.52 mmol) in DMF (10 mL) was added Pd(PPh₃)₄ (610 mg,0.528 mmol). The solution was stirred for 20 min, thentributyl(vinyl)stannane (1.227 g, 3.87 mmol) was added. The reactionmixture was heated at 120° C. for 5 h. Aqueous NH₄Cl solution was addedto quench the reaction, followed by addition of EtOAc. The mixture wasfiltered through celite and the filtrate was washed with saturatedNaHCO₃ and NH₄Cl solutions. The organic layer was separated, dried overNa₂SO₄ and concentrated to give the crude product, which was purifiedwith Analogix system on silica gel (hexanes:EtOAc) to afford 210 mg(20%) of the title compound. LCMS (method B): [MH]⁺=288, t_(R)=2.05 min.

1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine-6-carbaldehyde(38.2)

To a mixture of6-((6-vinyl-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (100mg, 0.347 mmol) and 2,6-dimethylpyridine (74.3 mg, 0.694 mmol) was addeda solution of osmium(VIII) oxide (297 mg, 1.387 mmol) in water (1.333mL), followed by addition of a solution of sodium periodate (88 mg, 6.94μmol) in 1,4-dioxane (4 mL). The reaction mixture was stirred at rt for10 h. The solvent was removed in vacuo and DCM was added to dilute theresidue. The resulting solution was washed with saturated NaHCO₃solution, NH₄Cl and brine. The organic layer was separated, dried overNa₂SO₄, and concentrated to give the crude product which was purifiedwith Analogix system on silica gel (hexanes:EtOAc) to afford 45 mg (43%)of the title compound. LCMS (method B): [MH]⁺=291, t_(R)=1.00 min.

(E)-1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine-6-carbaldehydeO-2-hydroxyethyl oxime (Example 38)

The title compound was prepared from1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine-6-carbaldehydeand 2-(aminooxy)ethanol hydrochloride in 45% yield using the sameprocedure as described in the synthesis of example 22. ¹H-NMR (400 MHz,CD₃OD), δ ppm 9.27 (s, 1H), 8.84 (m, 1H), 8.36 (s, 1H), 8.34 (d, 1H),8.01 (d, 1H), 8.00 (s, 1H), 7.85 (d, 1H), 7.53 (dd, 1H), 6.20 (s, 2H),4.39 (t, 2H), 3.87 (t, 2H). LCMS (method B): [MH]⁺=350, t_(R)=1.94 min.

Example 39 Example 39-R, Example 39-S(E)-1-(3-(1-(6-Fluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime

1-(6-Chloroimidazo[1,2-b]pyridazin-3-yl)-1-(6-fluoro-1-methyl-1H-indazol-5-yl)ethanol(39.1)

To a solution of 5-bromo-6-fluoro-1-methyl-1H-indazole (intermediate L)(1.800 g, 7.86 mmol) in THF (79 mL) at −100° C. was added n-BuLi (5.40mL, 8.64 mmol) dropwise. After stirring for 1 h at −100° C., a solutionof 1-(6-chloroimidazo[1,2-b]pyridazin-3-yl)ethanone (intermediate M)(1.691 g, 8.64 mmol) in THF (20 mL) was added dropwise. The reactionsolution was stirred for additional 2 h and quenched with NH₄Cl (aq).The resulting mixture was extracted with EtOAc. The combined organiclayers were washed with NH₄Cl (aq), dried over Na₂SO₄ and concentratedin vacuo to afford the crude product which was purified by columnchromatography (hexanes:EtOAc) to give the title compound in 34% yield.LCMS (method B): [MH]⁺=346, t_(R)=2.14 min.

6-Chloro-3-(1-(6-fluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazine(39.2)

A mixture of1-(6-chloroimidazo[1,2-b]pyridazin-3-yl)-1-(6-fluoro-1-methyl-1H-indazol-5-yl)ethanol(1.1 g, 3.18 mmol), diiodine (2.019 g, 7.95 mmol) and phosphinic acid(0.840 g, 12.73 mmol) in acetic acid (10 mL) was heated at 120° C. for 5h. After cooling, the reaction mixture was concentrated in vacuo. Theresidue was taken with water and adjusted to pH 8 with aqueous NaOH.Then the mixture was extracted with DCM, dried over Na₂SO₄ andconcentrated. The residue was purified with column chromatography(MeOH:EtOAc) to give 900 mg (60%) of the title compound. LCMS (methodB): [MH]⁺=330, t_(R)=2.59 min.

6-(1-Ethoxyvinyl)-3-(1-(6-fluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazine(39.3)

To a solution of6-chloro-3-(1-(6-fluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazine(900 mg, 1.910 mmol) in DMF (8 mL) was added Pd(Ph₃P)₄ (221 mg, 0.191mmol). The mixture was stirred for 20 min, andtributyl(1-ethoxyvinyl)stannane (784 mg, 2.102 mmol) was added. Theresulting mixture was heated at 100° C. until LC-MS showed the reactionwas complete. The reaction mixture was filtered through celite and thesolid was washed with ether. The combined filtrate was washed withwater, dried over Na₂SO₄, and concentrated. The residue was purified bycolumn chromatography with gradient hexane:EtOAc to give 450 mg (52%) ofthe title compound.

1-(3-(1-(6-Fluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone(39.4)

To a solution of the6-(1-ethoxyvinyl)-3-(1-(6-fluoro-1-methyl-1H-indazol-5-yl)ethyl)-imidazo[1,2-b]pyridazine(450 mg, 0.985 mmol) in acetic acid (8 mL) was added 3N HCl (0.5 mL).The solution was stirred at rt for 2 h and the solvent was removed underreduced pressure. The residue was diluted with water and its pH wasadjusted to basic with aqueous NaHCO₃ solution and extracted with DCM.The organic layer was washed with NaHCO₃ (aq) and brine, dried overNa₂SO₄, and concentrated in vacuo. The residue was purified by columnchromatography to give 300 mg (81%) of the title compound as a yellowsolid. LCMS (method B): [MH]⁺=338, t_(R)=2.49 min.

(E)-1-(3-(1-(6-Fluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime (Example 39, Example 39-R, Example 39-S)

To a solution of1-(3-(1-(6-fluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone(100 mg, 0.267 mmol) in methanol (10 mL) was added 2-(aminooxy)ethanolhydrochloride (30.3 mg, 0.267 mmol). Triethyl amine was added dropwiseto adjust the pH to 5˜6. The reaction mixture was stirred at 30° C. for20 h. The solvent was removed in vacuo and the residue was dissolved inDCM, washed with NaHCO₃ (aq) and brine. The organic layer was dried overNa₂SO₄ and concentrated in vacuo to afford the crude product which waspurified by chromatography on silica gel to afford 19 mg (17%) of thetitle compound. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.01 (d, 1H), 7.91 (s,1H), 7.77 (s, 1H), 7.58 (d, 1H), 7.50 (s, 1H), 7.49 (d, 1H), 4.91 (q,1H), 4.76 (t, 1H), 4.20 (t, 2H), 3.95 (s, 3H), 3.65 (m, 2H), 2.13 (s,3H), 1.76 (d, 3H). LCMS (method B): [MH]⁺=397, t_(R)=2.50 min. Chiralseparation (method K) provided enantiomeric pure compounds example 39-Rand example 39-S.

Example 40(E)-1-(3-((6-Fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime

6-Chloroimidazo[1,2-b]pyridazin-3-yl)(6-fluoro-1-methyl-1H-indazol-5-yl)methanol(40.1)

The title compound was prepared as a yellow solid in analogy to thesynthesis of compound 39.1 from6-chloroimidazo[1,2-b]pyridazine-3-carbaldehyde. LCMS (method B):[MH]⁺=332, t_(R)=2.09 min.

6-Chloro-3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine(40.2)

The title compound was prepared as a yellow solid in analogy to thesynthesis of compound 39.2 from(6-chloroimidazo[1,2-b]pyridazin-3-yl)(6-fluoro-1-methyl-1H-indazol-5-yl)methanol.LCMS (method B): [MH]⁺=316, t_(R)=2.56 min.

6-(1-Ethoxyvinyl)-3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine(40.3)

The title compound was prepared in analogy to the synthesis of compound39.3 from6-chloro-3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine.

1-(3-((6-Fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanone(40.4)

The title compound was prepared as a white solid in analogy to thesynthesis of compound 39.4 from6-(1-ethoxyvinyl)-3-(6-fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine.LCMS (method B): [MH]⁺=324, t_(R)=2.41 min.

(E)-1-(3-((6-Fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime (Example 40)

To a solution of1-(3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanone(50 mg, 0.155 mmol) in methanol (7 mL) was added 2-(aminooxy)ethanolhydrochloride (17.6 mg, 0.155 mmol). Triethyl amine was added dropwiseto adjust the pH to 5-6. The reaction mixture was stirred at 30° C. for20 h. The solvent was removed in vacuo and the residue was dissolved inDCM, washed with NaHCO₃ (aq) and brine. The organic layer was dried overNa₂SO₄ and concentrated in vacuo to afford the crude product which waspurified by column chromatography to afford 43 mg (70%) of the titlecompound. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.05 (d, 1H), 7.97 (s, 1H),7.70 (d, 1H), 7.63 (d, 1H), 7.62 (s, 1H), 7.53 (d, 1H), 4.75 (t, 1H),4.43 (s, 1H), 4.23 (t, 2H), 3.97 (s, 3H), 3.68 (q, 2H), 2.28 (s, 3H).LCMS (method B): [MH]⁺=383, t_(R)=2.45 min.

Example 41(E)-1-(3-(Quinolin-6-ylmethyl)-[1,2,4]-triazolo[4,3-b]pyridazin-6-yl)ethanoneO-methyl oxime

6-((6-(1-Ethoxyvinyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline(41.1)

A solution of6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline(intermediate O) (50 mg, 0.169 mmol) and tributyl(1-ethoxyvinyl)stannane(0.06 mL, 0.178 mmol) in DMF (6 mL) was purged with N₂ for 30 min andthen Pd(PPh₃)₄ (9.77 mg, 0.0085 mmol) was added. The resulting solutionwas heated at 100° C. for 3 h. The reaction mixture was quenched withwater, extracted with EtOAc three times. The organic layers werecombined, washed with KF solution and brine, dried over Na₂SO₄. Afterconcentration, the crude was used in the next step without furtherpurification. LCMS (method A): [MH]⁺=332.1, t_(R)=4.969 min.

1-(3-(Quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone(41.2)

To a solution of6-((6-(1-ethoxyvinyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinolinein MeOH (30 mL) was added excess 3N HCl solution. The solution wasstirred at rt overnight and neutralized with saturated NaHCO₃ solution.Organic solvent was evaporated and the residue was extracted with EtOActhree times. Organic layers were combined, washed with brine and driedover Na₂SO₄. Solvent was evaporated and the crude was purified by columnchromatography (DCM:MeOH=95:5) to give the title compound as yellowsolid (51.3%). LCMS (method B): [MH]⁺=304.1, t_(R)=1.708 min.

(E)-1-(3-(Quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-methyl oxime (Example 41)

A solution of1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone(60 mg, 0.198 mmol) and O-methylhydroxylamine (49.6 mg, 0.593 mmol) inMeOH (10 mL) was stirred at rt overnight. Solvent was evaporated and thecrude was purified by HPLC (acidic with 0.05% TFA and then neutralizedto free base) to give 40 mg (60.8%) of the title compound as a whitesolid. ¹H-NMR (400 MHz, MeOH-d₄ δ ppm 8.82 (s, 1H), 8.32 (d, 1H), 8.12(d, 1H), 7.98 (m, 3H), 7.84 (d, 1H), 7.54 (m, 1H), 4.83 (s, 2H), 4.09(s, 3H), 2.28 (s, 3H). LC-MS (method B): [MH]⁺=333.1, t_(R)=2.34 min.

Example 42(E)-1-(3-(Quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-ethyl oxime

A solution of1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone(41.2) (30 mg, 0.099 mmol) and O-ethylhydroxylamine (18.12 mg, 0.297mmol) in 5 mL of MeOH was stirred at rt overnight. Solvent wasevaporated and the crude was purified by HPLC (acidic with 0.05% TFA) togive 15.8 mg (46.1%) of the title compound as a white TFA salt. ¹H-NMR(400 MHz, MeOH-d₄ δ ppm 9.05 (s, 1H), 8.85 (d, 1H), 8.23 (s, 1H), 8.12(m, 3H), 7.98 (d, 1H), 7.89 (m, 1H), 4.91 (s, 2H), 4.36 (q, 2H), 2.30(s, 3H), 1.36 (t, 3H). LC-MS (method B): [MH]⁺=347.1.1, t_(R)=2.50 min.

Example 43(E)-1-(3-(Quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-1-hydroxypropan-2-yl oxime

A solution of1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone(41.2) (40 mg, 0.132 mmol) and 2-(aminooxy)propan-1-ol (intermediate Q)(33.6 mg, 0.264 mmol) in 15 mL of MeOH was stirred at it overnight.Solvent was evaporated and the crude was purified by HPLC (basic with0.05% NH₄OH) to give 22 mg (44%) of the title compound as a white solid.¹H-NMR (400 MHz, MeOH-d₄ δ ppm 8.82 (s, 1H), 8.33 (d, 1H), 8.12 (d, 1H),7.98 (t, 3H), 7.84 (d, 1H), 7.55 (m, 1H), 4.84 (s, 2H), 4.50 (m, 1H),3.72 (d, 2H), 2.32 (s, 3H), 1.33 (d, 3H). LC-MS (method B): [MH]⁺=377.0,t_(R)=1.867 min.

Example 44(E)-1-(3-(Quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime

Hydrazine monohydrate (3.96 mg, 0.124 mmol) was added to a solution of2-(2-hydroxyethoxy)isoindoline-1,3-dione (produced with a similarprocedure for intermediate B) (25.6 mg, 0.124 mmol) in 5 mL of MeOH. Thesolution was heated at reflux for 2 h and then cooled to rt. Whiteprecipitate was filtered off and1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone(41.2) (15 mg, 0.049 mmol) was added. The pH value of the solution wasadjusted to 5-6 with 1N HCl solution. The reaction solution was thenstirred at it for 2 h. Solvent was evaporated and the crude was purifiedby HPLC (acidic with 0.05% TFA) to give 8 mg (44.5%) of the titlecompound as a white TFA salt. ¹H-NMR (400 MHz, MeOH-d₄) δ ppm 9.09 (s,1H), 8.93 (d, 1H), 8.27 (s, 1H), 8.16 (m, 3H), 7.98 (d, 1H), 7.93 (m,1H), 4.92 (s, 2H), 4.38 (t, 2H), 3.86 (t, 2H), 2.34 (s, 3H). LC-MS(method B): [MH]⁺=363.1, t_(R)=2.31 min.

Example 45(E)-1-(3-(Quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-1,3-dihydroxypropan-2-yl oxime

The title compound (12 mg, 28.6%) was synthesized from2-(1,3-dihydroxypropan-2-yloxy)isoindoline-1,3-dione (intermediate B)(152 mg, 0.643 mmol, isomer mixture), hydrazine monohydrate (14 mg, 0.27mmol) and1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone(41.2) (30 mg, 0.11 mmol) using the same procedure as described in thesynthesis of example 44. After purification by HPLC (acidic with 0.05%TFA, then neutralized to basic), the title compound was obtained as awhite solid. ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.89 (d, 1H), 8.12 (d, 1H),8.08 (d, 1H), 7.97 (d, 1H), 7.86 (s, 1H), 7.82 (d, 1H), 7.73 (d, 1H),7.42 (m, 1H), 4.77 (s, 2H), 4.49 (m, 1H), 4.00 (dd, 4H), 2.33 (s, 3H).LC-MS (method B): [MH]⁺=393.2, t_(R)=1.708 min.

Example 46(E)-1-(3-(Quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-2,3-dihydroxypropyl oxime

The title compound (6 mg, 14.3%) was synthesized from2-(2,3-dihydroxypropoxy)iso-indoline-1,3-dione (intermediate B) (152 mg,0.643 mmol, isomer mixture), hydrazine monohydrate (14 mg, 0.27 mmol)and1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone(41.2) (30 mg, 0.11 mmol) using the same procedure as described in thesynthesis of example 44. After purification by HPLC (acidic with 0.05%TFA, then neutralized to basic), the title compound was obtained as awhite solid. ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.89 (d, 1H), 8.12 (d, 1H),8.08 (d, 1H), 7.98 (d, 1H), 7.86 (s, 1H), 7.83 (d, 1H), 7.74 (d, 1H),7.42 (m, 1H), 4.78 (s, 2H), 4.37 (d, 2H), 4.15 (m, 1H), 3.75 (m, 2H),2.32 (s, 3H). LC-MS (method B): [MH]⁺=393.2, t_(R)=1.841 min.

Example 47(E)-1-(3-(Quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-3-(trifluoromethyl)phenyl oxime

Hydrazine monohydrate (2.6 mg, 0.052 mmol) was added to a solution of2-(3-(trifluoromethyl)phenoxy)isoindoline-1,3-dione (Organic Lett.,2001, 31, 139) (19.75 mg, 0.064 mmol) in 5 mL of MeOH. The solution washeated at reflux for 2 h and then cooled to rt. White precipitate wasfiltered off and1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone(41.2) (15 mg, 0.049 mmol) was added. The pH value of solution wasadjusted to 5-6 with 1N HCl solution. The reaction solution was stirredat it overnight. Solvent was evaporated and the crude was purified byHPLC (acidic with 0.05% TFA) to give the title compound as a white solid(TFA salt, 15 mg, 65.6%). ¹H-NMR (400 MHz, MeOH-d₄) δ ppm 9.07 (s, 1H),8.90 (d, 1H), 8.26 (m, 2H), 8.16 (m, 3H), 7.91 (m, 1H), 7.60 (m, 3H),7.43 (d, 1H), 4.96 (s, 2H), 2.59 (s, 3H). LC-MS (method E): [MH]⁺=463.1,t_(R)=6.03 min.

Example 48(E)-1-(3-(Quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-phenyl oxime

Hydrazine monohydrate (5.45 mg, 0.109 mmol) was added to a solution of2-phenoxyisoindoline-1,3-dione (Organic Lett, 2001, 31, 139) (30.8 mg,0.129 mmol) in 10 mL of MeOH. The solution was heated at reflux for 2 hand then cooled to rt. White precipitate was filtered off and1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone(41.2) (30 mg, 0.1 mmol) was added. The pH value of solution wasadjusted to 5-6 with 1N HCl solution. The reaction solution was thenstirred at it overnight. Solvent was evaporated and the crude waspurified by HPLC (acidic with 0.05% TFA) to give 23 mg (59%) of thetitle compound as a white solid (TFA salt). ¹H-NMR (400 MHz, CDCl₃) δppm 9.23 (d, 1H), 8.68 (d, 1H), 8.53 (d, 1H), 8.15 (m, 3H), 8.04 d, 1H),7.83 (m, 1H), 7.40 (t, 2H), 7.29 (m, 2H), 7.15 (t, 1H), 4.92 (s, 2H),2.56 (s, 3H). LC-MS (method H): [MH]⁺=395.2, t_(R)=2.42 min.

Example 49(E)-1-(3-(Quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-benzyl oxime

The title compound was prepared from1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone(41.2) and O-benzylhydroxylamine (intermediate H) using the sameprocedure described in the synthesis of example 41. ¹H-NMR (400 MHz,CHCl₃-d₁) δ ppm 8.87 (d, 1H), 8.06 (m, 2H), 7.95 (d, 1H), 7.84 (s, 1H),7.80 (m, 2H), 7.38 (m, 6H), 5.30 (s, 2H), 4.77 (s, 2H), 2.32 (s, 3H).LC-MS (method J): [MH]⁺=409.1, t_(R)=2.42 min.

Example 50(E)-1-(3-(Difluoro(quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime

1-(3-(Difluoro(quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone(50.1)

The title compound as a light yellow oil (180 mg, 30%, 80% purity) wassynthesized from6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)quinoline(intermediate R) (500 mg, 1.507 mmol), tributyl(1-ethoxyvinyl)stannane(2.55 mL, 7.54 mmol) and PdCl₂(PPh₃)₂ (106 mg, 0.151 mmol) in1,4-dioxane using the similar procedure as described in the synthesis ofcompound 41.2. ¹H-NMR (400 MHz, MeOH-d₄) δ ppm 9.17 (s, 1H), 8.91 (d,1H), 8.65 (s, 1H), 8.43 (d, 1H), 8.28 (q, 2H), 7.96 (d, 1H), 7.92 (m,1H), 2.61 (s, 3H). LCMS (method B): [MH]⁺=340.1, t_(R)=2.16 min.

(E)-1-(3-(Difluoro(quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime (example 50)

A solution of1-(3-(difluoro(quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone(54 mg, 0.159 mmol) and 2-(aminooxy)ethanol (intermediate S) (36.1 mg,0.318 mmol) in 8 mL of MeOH was stirred at it overnight. Solvent wasevaporated and the residue was partitioned between water and EtOAc.Aqueous layer was extracted with EtOAc twice. Organic layers werecombined, washed with brine and dried over Na₂SO₄. Solvent wasevaporated and the crude was purified by HPLC (basic with 0.05% NH₄OH)to give 35 mg (55%) of the title compound as a white solid. ¹H-NMR (400MHz, MeOH-d₄) δ ppm 8.98 (d, 1H), 8.52 (d, 1H), 8.43 (s, 1H), 8.23 (d,1H), 8.19 (d, 1H), 8.06 (d, 1H), 8.04 (d, 1H), 7.66 (m, 1H), 4.36 (m,2H), 3.84 (m, 2H), 2.18 (s, 3H). LCMS (method B): [MH]⁺=398.9,t_(R)=2.29 min.

Example 51 Example 51-R, Example 51-S(E)-1-(3-(1-(4,6-Difluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime

1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(4,6-difluoro-1-methyl-1H-indazol-5-yl)-ethanol(51.1)

To a solution of 4,6-difluoro-1-methyl-1H-indazole (intermediate P) (600mg, 3.57 mmol) in anhydrous THF (20 mL) at −78° C. was added n-BuLi(1.6M solution in hexane, 2.56 mL, 4.1 mmol). The solution was stirredat this temperature for 1 h and then a solution of1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethanone (intermediate M) (698mg, 3.57 mmol) in anhydrous THF (10 mL) was added dropwise. Theresulting solution was stirred at this temperature for 3 h and allowedto warm to it slowly and stirred overnight. The reaction mixture wasquenched with water, extracted with EtOAc three times. The organiclayers were combined and washed with brine, dried over Na₂SO₄. The crudewas purified by flash chromatography (DCM: MeOH=95:5) to give 530 mg(41%) of the title compound as yellow oil. ¹H-NMR (400 MHz, CDCl₃) δ ppm8.05 (d, 1H), 8.0 (s, 1H), 7.85 (s, 1H), 7.1 (d, 1H), 6.85 (d, 1H), 4.0(s, 3H), 2.3 (s, 3H). LCMS (method B): [MH]⁺=363.9, t_(R)=2.15 min.

6-Chloro-3-[1-(4,6-difluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine(51.2)

A solution of1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(4,6-difluoro-1-methyl-1H-indazol-5-yl)-ethanol(530 mg, 1.457 mmol), Iodine (925 mg, 3.64 mmol) and phosphinic acid(50%, 0.556 mL) in 20 mL of acetic acid was heated at 110° C. for 2 h.Solvent was evaporated and the residue was dissolved in water,neutralized with saturated NaHCO₃ solution and extracted with DCM threetimes. Organic layers were combined and washed with brine, dried overNa₂SO₄. Solvent was then evaporated and the crude was purified by flashchromatography (hexane: EtOAc=1:2) to give the title compound as lightyellow solid (320 mg, 63.2%). ¹H-NMR (400 MHz, MeOH-d₄) δ ppm 8.03 (s,1H), 8.0 (d, 1H), 7.8 (s, 1H), 7.23 (d, 1H), 7.19 (d, 1H), 5.1 (q, 1H),4.0 (s, 3H), 1.92 (d, 3H). LCMS (method B): [MH]⁺=347.9, t_(R)=2.69 min.

3-[1-(4,6-Difluoro-1-methyl-1H-indazol-5-yl)-ethyl]-6-(1-ethoxy-vinyl)-imidazo[1,2-b]pyridazine(51.3)

A solution of6-chloro-3-[1-(4,6-difluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine(80 mg, 0.23 mmol) and tributyl(1-ethoxyvinyl)stannane (0.234 mL, 0.69mmol) in 15 mL of DMF was purged with N₂ for 30 min and then Pd(PPh₃)₄(80 mg, 0.069 mmol) was added and the solution was heated at 95° C.overnight. After the reaction was complete, it was quenched with water,extracted with EtOAc three times. The organic layers were combined,washed with KF solution then brine, dried over Na₂SO₄. Solvent wasevaporated and the crude (80 mg, 90%) was used in the next step withoutfurther purification. LCMS (method C): [MH]⁺=384.0, t_(R)=4.67 min

1-(3-(1-(4,6-Difluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone(51.4)

2 mL of 3N HCl solution was added to a solution of3-[1-(4,6-difluoro-1-methyl-1H-indazol-5-yl)-ethyl]-6-(1-ethoxy-vinyl)-imidazo[1,2-b]pyridazinein 10 mL of MeOH. The reaction solution was stirred at rt for 3 h andthen neutralized with saturated NaHCO₃ solution. Solvent was evaporatedand the residue was purified by chromatography (DCM: MeOH=10:1) to givethe title compound as yellow solid (30 mg, 41%). LCMS (method C):[MH]⁺=355.9, t_(R)=3.75 min.

(E)-1-(3-(1-(4,6-Difluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime (Example 51, Example 51-R, Example 51-S)

A solution of1-(3-(1-(4,6-difluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone(110 mg, 0.31 mmol) and 2-(aminooxy)ethanol (intermediate S) (35.1 mg,0.31 mmol) in 10 mL of MeOH was stirred at it overnight. Solvent wasevaporated and the residue was partitioned between water and EtOAc.Aqueous layer was extracted with EtOAc twice. Organic layers werecombined, washed with brine and dried over Na₂SO₄. Solvent wasevaporated and the crude was purified by HPLC (basic with 0.05% NH₄OH)to give 55 mg (43%) of the title compound as white solid. ¹H-NMR (400MHz, MeOH-d₄) δ ppm 8.01 (s, 1H), 7.88 (d, 1H), 7.78 (s, 1H), 7.76 (s,1H), 7.16 (d, 1H), 5.16 (m, 1H), 4.29 (m, 2H), 3.99 (s, 3H), 3.82 (m,2H), 2.17 (s, 3H), 1.95 (d, 3H). LCMS (method B): [MH]⁺=415.0,t_(R)=2.64 min. Chiral separation (method G) provided enantiomeric purecompounds example 51-R and example 51-S.

Example 52(E)-1-(3-((4,6-Difluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime

(6-Chloroimidazo[1,2-b]pyridazin-3-yl)(4,6-difluoro-1-methyl-1H-indazol-5-yl)methanol(52.1)

The title compound as a yellow solid (60 mg, 41%) was synthesized from(intermediate P) (70 mg, 0.416 mmol) and6-chloroimidazo[1,2-b]pyridazine-3-carbaldehyde (intermediate N) (76 mg,0.416 mmol) using the same procedure as described in the synthesis ofcompound 51.1. ¹H-NMR (400 MHz, MeOH-d₄) δ ppm 8.08 (s, 1H), 8.03 (d,1H), 7.85 (s, 1H), 7.26 (q, 2H), 6.76 (s, 1H), 4.03 (s, 3H). LCMS(method B): [MH]⁺=349.9, t_(R)=2.12 min.

6-Chloro-3-((4,6-difluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine(52.2)

The title compound as a light yellow solid (370 mg, 78%) was synthesizedfrom(6-chloroimidazo[1,2-b]pyridazin-3-yl)(4,6-difluoro-1-methyl-1H-indazol-5-yl)methanol(500 mg, 1.43 mmol), iodine (907 mg, 3.57 mmol) and phosphinic acid(50%, 0.55 mL) using the same procedure as described in the synthesis ofcompound 51.2. ¹H-NMR (400 MHz, MeOH-d₄) δ ppm 8.07 (s, 1H), 8.01 (d,1H), 7.44 (s, 1H), 7.29 (d, 1H), 7.27 (d, 1H), 4.46 (s, 2H), 4.04 (s,3H). LCMS (method B): [MH]⁺=333.9, t_(R)=2.68 min.

1-(3-((4,6-Difluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanone(52.3)

The title compound as a light yellow solid (350 mg, 71.3%) wassynthesized from6-chloro-3-((4,6-difluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine(360 mg, 1.079 mmol), tributyl(1-ethoxyvinyl)stannane (1.095 mL, 3.24mmol) and Pd(PPh₃)₄ (374 mg, 0.324 mmol) using the same procedure asdescribed in the synthesis of compound 51.3 and 51.4. ¹H-NMR (400 MHz,MeOH-d₄) δ ppm 8.09 (s, 1H), 8.07 (s, 1H), 7.78 (d, 1H), 7.71 (s, 1H),7.26 (d, 1H), 4.59 (s, 2H), 4.02 (s, 3H), 2.74 (s, 3H). LCMS (method B):[MH]⁺=342.0, t_(R)=2.39 min.

(E)-1-(3-((4,6-Difluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime (Example 52)

A solution of1-(3-((4,6-difluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanone(62 mg, 0.136 mmol) and 2-(aminooxy)ethanol (intermediate S) (77 mg,0.681 mmol) in 3 mL of MeOH and 2 mL of DCM was stirred at rt for 2days. Solvent was evaporated to give a residue, which was purified bychromatography (DCM:MeOH 10:1) and recrystallized from MeOH to give thetitle compound as a white solid (32 mg, 59%). ¹H-NMR (400 MHz, DMSO-d₆)δ ppm 8.16 (s, 1H), 8.04 (d, 1H), 7.62 (t, 2H), 7.48 (d, 1H), 4.44 (s,2H), 4.24 (t, 2H), 4.00 (s, 3H), 3.68 (m, 2H), 2.29 (s, 3H). LCMS(method E): [MH]⁺=401.1, t_(R)=5.591 min.

Example 53 Example 53-S and Example 53-R(E)-1-(3-(1-(5,7-Difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime

2-(5,7-Difluoro-quinolin-6-yl)-propionic acid methyl ester (53.1)

To a solution of LDA (1.2 M in THF, 9.5 mL, 11.4 mmol) in dry THF (30mL) at −78° C. was added a solution of(5,7-difluoroquinolin-6-yl)-acetic acid methyl ester (2.12 g, 9.5 mmol)in THF (20 mL) dropwise. After 30 min, MeI (0.9 mL, 14.2 mmol) was addeddropwise, and the reaction mixture was allowed to rise to 0° C.naturally. After 1 h, the reaction was quenched by saturated aqueousNaHCO₃ solution, and extracted with EtOAc. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄, filtered, concentrated, andpurified by column chromatography to afford 2.272 g (95%) of the titlecompound as a pale yellow solid. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.93(d, 1H), 8.39 (dd, 1H), 7.61 (dd, 1H), 7.41-7.46 (m, 1H), 4.29 (q, 1H),3.73 (s, 3H), 1.62 (d, 3H). LCMS (method A): [MH]⁺=252, t_(R)=5.09 min.(5,7-difluoroquinolin-6-yl)-acetic acid methyl ester was synthesizedusing the method described in WO2008/144767 p 108 (intermediate 2),followed by the method described for Intermediate 12, step 1WO2008/144767 p 114.

2-(5,7-Difluoro-quinolin-6-yl)-propionic acid hydrazide (53.2)

2-(5,7-Difluoro-quinolin-6-yl)-propionic acid methyl ester (2.270 g,9.57 mmol) in ethanol (25 mL) was added hydrazine monohydrate (3 mL, 96mmol), and the reaction mixture was stirred at 25° C. overnight. Solventwas removed under reduced pressure, and the residue was used withoutfurther purification. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.06 (s, 1H), 8.97(dd, 1H), 8.45 (d, 1H), 7.58-7.67 (m, 2H), 4.23 (br s, 2H), 4.08 (q,1H), 1.51 (d, 3H). LCMS (method A): [MH]⁺=252, t_(R)=3.82 min.

6-[1-(6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline(53.3)

A solution of 2-(5,7-difluoro-quinolin-6-yl)-propionic acid hydrazide(2.404 g, 9.404 mmol) and 3,6-dichloropyridazine (2.138 g, 14.35 mmol)in butan-1-ol (60 mL) was stirred at 135° C. in a sealed tube overnight.Solvent was removed under reduced pressure, and the residue was purifiedby column chromatography to afford 1.476 g (45% for two steps) of thetitle compound as a pale yellow solid. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm8.93 (dd, 1H), 8.36 (dd, 1H), 8.07 (d, 1H), 7.62 (dd, 1H), 7.43 (dd,1H), 7.05 (d, 1H), 5.26 (q, 1H), 2.13 (d, 1H). LCMS (method A):[MH]⁺=346, t_(R)=5.00 min.

6-{1-[6-(1-Ethoxy-vinyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-ethyl}-5,7-difluoro-quinoline(53.4)

A solution of6-[1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline(1.500 g, 4.34 mmol) in dioxane (60 mL) was purged with argon for 3 min,followed by addition of tributyl-(1-ethoxy-vinyl)-stannane (2.2 mL, 6.51mmol) and PdCl₂(PPh₃)₂ (150 mg, 0.21 mmol) sequentially. The mixture waspurged with argon for another half min. The reaction mixture was stirredat 80-85° C. for 6 h under argon. LC/MS showed the reaction wascomplete. The reaction mixture was diluted with EtOAc, washedsuccessively with aqueous KF solution (2×25 mL), water, and brine. Theorganic phase was dried over anhydrous Na₂SO₄, concentrated to give thecrude title compound, which was used without further purification. LCMS(method A): [MH]⁺=382, t_(R)=5.05 min.

1-{3-[1-(5,7-Difluoro-quinolin-6-yl)-ethyl]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl}-ethanone(53.5)

The crude6-{1-[6-(1-ethoxy-vinyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-ethyl}-5,7-difluoro-quinolineobtained from the previous step was dissolved in HOAc (50 mL), 3N HClaqueous solution (5 mL) was added. The reaction mixture was stirred atrt overnight. LC/MS showed the reaction was complete. Solvent wasremoved under reduced pressure. EtOAc was added, and cold 1N NaOHaqueous solution was added slowly until pH 8-9. The mixture wasextracted with EtOAc, and the combined organic layers were dried overanhydrous Na₂SO₄, filtered, concentrated, and purified by columnchromatography to afford 1.0 g (65% for two steps) of the title compoundas a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.92 (dd, 1H), 8.32(d, 1H), 8.14 (d, 1H), 7.68 (d, 1H), 7.61 (d, 1H), 7.42 (dd, 1H), 5.32(q, 1H), 2.43 (s, 3H), 2.21 (d, 3H). LCMS (method A): [MH]⁺=354,t_(R)=4.42 min.

(E)-1-(3-(1-(5,7-Difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime (example 53)

To a suspension of1-{3-[1-(5,7-difluoro-quinolin-6-yl)-ethyl]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl}-ethanone(4.2 g, 11.9 mmol) in methanol (250 mL) was added 2-(aminooxy)ethanolhydrochloride (intermediate S) (2.70 g, 23.8 mmol). The mixture wasstirred at rt overnight. LC-MS showed the reaction was complete. Anaqueous 1N NaOH solution was added slowly until pH 8-9. The mixture wasconcentrated, extracted with EtOAc, washed with water and brine. Theorganic layer was dried over anhydrous Na₂SO₄, filtered, concentrated,and purified by gradient column chromatography (EtOAc:hexane=2:1, then100% EtOAc, and then MeOH:EtOAc=1:12 as eluent) to afford 4.8 g (98%) ofthe title compound as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm8.97 (dd, 1H), 8.44 (m, 1H), 8.25 (d, 1H), 7.64-7.70 (m, 2H), 7.59 (dd,1H), 5.25 (q, 1H), 4.70 (t, 1H), 4.19 (t, 2H), 3.62 (dd, 2H), 2.02 (d,3H), 1.88 (s, 3H). LCMS (method A): [MH]⁺=413, t_(R)=5.09 min.

(E)-1-(3-(1-(5,7-Difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime (Example 53-S and Example 53-R)

The title compounds were obtained by separation of racemic mixture(E)-1-(3-(1-(5,7-difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime (4.2 g) with Method I. Data for example 53-5 (1.5g): ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.96 (d, 1H), 8.44 (d, 1H), 8.25 (d,1H), 7.64-7.71 (m, 2H), 7.59 (dd, 1H), 5.25 (q, 1H), 4.70 (t, 1H), 4.19(t, 2H), 3.62 (dd, 2H), 2.02 (d, 3H), 1.88 (s, 3H). LCMS (method A):[MH]⁺=413, t_(R)=5.09 min. Data for example 53-R (1.6 g): ¹H-NMR (400MHz, DMSO-d₆) δ ppm 8.96 (d, 1H), 8.44 (d, 1H), 8.25 (d, 1H), 7.64-7.71(m, 2H), 7.59 (dd, 1H), 5.25 (q, 1H), 4.70 (t, 1H), 4.19 (t, 2H), 3.62(dd, 2H), 2.02 (d, 3H), 1.88 (s, 3H). LCMS (method A): [MH]⁺=413,t_(R)=5.09 min.

Example 54(E)-1-(3-((5,7-Difluoroquinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime

The title compound was prepared using the same procedure as described inthe synthesis of example 53. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.00 (d,1H), 8.50 (d, 1H), 8.27 (d, 1H), 7.72-7.76 (m, 2H), 7.63 (dd, 1H), 4.78(s, 3H), 4.27 (t, 2H), 3.69 (t, 2H), 2.20 (s, 3H). LCMS (method A):[MH]⁺=399, t_(R)=4.86 min.

Example 55(E)-1-(3-((5,7-Difluoroquinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-2-fluoroethyl oxime

To a solution of(E)-1-(3-((5,7-difluoroquinolin-6-yl)methyl)-[1,2,4]-triazolo[4,3-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime (example 54) (20 mg, 0.05 mmol) in dry DCM (4 mL)was added bis-(2-methoxyethyl)aminosulfur trifluoride (a 3.2 M solutionin toluene, 0.13 mL, 0.4 mmol) at 0° C. The reaction mixture was stirredat 0° C. for 1 h, and then at 35° C. overnight. LC-MS showed thereaction was complete, and 5 mL of saturated NaHCO₃ solution was added.The mixture was extracted with DCM; the organic phase was dried overNa₂SO₄, filtered, concentrated, and purified by column chromatography toafford 6.8 mg (34%) of the title compound as a white solid. ¹H-NMR (400MHz, CDCl₃) δ ppm 8.95 (dd, 1H), 8.41 (dd, 1H), 8.00 (d, 1H), 7.81 (d,1H), 7.66 (d, 1H), 7.46 (dd, 1H), 4.83 (s, 2H), 4.78 (dd, 1H), 4.67 (dd,1H), 4.56 (dd, 1H), 4.49 (dd, 1H), 2.33 (s, 3H). LCMS (method A):[MH]⁺=401, t_(R)=5.44 min.

Example 56(E)-1-(3-((5,7-Difluoroquinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-3-hydroxypropyl oxime

The title compound was prepared using the same procedure as described inthe synthesis of example 53. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.99 (dd,1H), 8.49 (dd, 1H), 8.26 (d, 1H), 7.72-7.75 (m, 2H), 7.62 (dd, 1H), 4.76(s, 2H), 4.52 (t, 1H), 4.32 (t, 2H), 3.48-3.53 (m, 2H), 2.18 (s, 3H),1.80-1.88 (m, 2H). LCMS (method A): [MH]⁺=413, t_(R)=5.21 min.

Example 57(E)-1-(3-((7-Fluoroquinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime

The title compound was prepared using the same procedure as described inthe synthesis of example 53. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.89 (d,1H), 8.36 (d, 1H), 8.29 (d, 1H), 8.06 (d, 1H), 7.74-7.81 (m, 2H), 7.51(dd, 1H), 4.77 (s, 3H), 3.68-3.70 (m, 2H), 2.23 (s, 3H). LCMS (methodA): [MH]⁺=381, t_(R)=4.66 min.

Example 58(E)-1-(3-((5-Fluoroquinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime

The title compound was prepared using the same procedure as described inthe synthesis of example 53. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.95 (d,1H), 8.50 (d, 1H), 8.27 (d, 1H), 7.85 (d, 1H), 7.70-7.81 (m, 2H), 7.63(dd, 1H), 4.78 (s, 2H), 4.26 (t, 2H), 4.09 (s br, 1H), 3.68-3.69 (m,2H), 2.23 (s, 3H). LCMS (method A): [MH]⁺=381, t_(R)=5.05 min.

Example 59(E)-1-(3-(1-(Quinolin-6-yl)cyclopropyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-ethyl oxime

Methyl 1-(quinolin-6-yl)cyclopropanecarboxylate (59.1)

LDA (1.8 M solution in toluene, 14.8 mL, 26.6 mmol) was added dropwiseto a solution of quinolin-6-yl-acetic acid methyl ester (2.14 g, 10.64mmol) in dry THF (40 mL) under nitrogen at −78° C. After 30 min,1,2-dibromoethane (2.40 g, 12.76 mmol) was added dropwise over 3 min.The resulting mixture was stirred for 1 h at rt, then quenched withsaturated aqueous NH₄Cl, extracted with DCM, washed with brine, driedover Na₂SO₄, and evaporated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting with EtOAc/hexanegradient to afford the title compound as a yellow solid (463 mg, 20%).¹H-NMR (400 MHz, CDCl₃) δ ppm 8.91 (dd, 1H), 8.12 (d, 1H), 8.07 (d, 1H),7.77-7.74 (m, 2H), 7.40 (dd, 1H), 3.65 (s, 3H), 1.73-1.71 (m, 2H),1.33-1.30 (m, 2H). LCMS (method A): [MH]⁺=228, t_(R)=4.37 min.

1-(Quinolin-6-yl)cyclopropanecarbohydrazide (59.2)

A solution of methyl 1-(quinolin-6-yl)cyclopropanecarboxylate (513 mg,2.26 mmol) and hydrazine monohydrate (3.39 g, 67.7 mmol) in 5 mL ofmethanol was heated at reflux overnight. After cooling, solvent wasremoved in vacuo to afford the title compound (513 mg, 100%). LCMS(method A): [MH]⁺=228, t_(R)=2.88 min.

6-(1-(6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)cyclopropyl)quinoline(59.3)

A sealed tube was charged with1-(quinolin-6-yl)cyclopropanecarbohydrazide (513 mg, 2.26 mmol),3,6-dichloro-pyridazine (437 mg, 2.93 mmol) and 5 mL of n-butanol. Themixture was heated at 140° C. for 12 h. After cooling, solvent wasremoved in vacuo and the residue was purified by flash chromatography onsilica gel eluting with EtOAc/methanol gradient to afford the titlecompound (196 mg, 41%). LCMS (method A): [MH]⁺=322, t_(R)=4.38 min.

1-(3-(1-(Quinolin-6-yl)cyclopropyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone(59.4)

A mixture of6-[1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-cyclopropyl]-quinoline(30 mg, 0.093 mmol), PdCl₂(PPh₃)₂ (6.5 mg, 0.0093 mmol) andtributyl(1-ethoxyvinyl)stannane (67 mg, 0.186 mmol) in 3 mL of1,4-dioxane was heated at 90° C. for 3 h under nitrogen. The reactionmixture was diluted with EtOAc, washed with aqueous KF. The organiclayer was dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was dissolved in HOAc and 3 N HCl, and the solution was stirredat rt for 3 h. The solvent was removed under reduced pressure and theresidue was dissolved in DCM, washed with saturated aqueous NaHCO₃ andbrine. The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with EtOAc/MeOH gradient to afford the titlecompound as a yellow solid. ¹H-NMR (400 MHz, CDCl₃) 3 ppm 8.89 (dd, 1H),8.13-8.04 (m, 3H), 7.93 (d, 1H), 7.87 (dd, 1H), 7.70 (d, 1H), 7.40 (dd,1H), 2.51 (s, 3H), 1.92-1.89 (m, 2H), 1.73-1.69 (m, 2H). LCMS (methodA): [MH]⁺=330, t_(R)=4.18 min.

(E)-1-(3-(1-(Quinolin-6-yl)cyclopropyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-ethyl oxime (example 59)

A solution of1-(3-(1-(quinolin-6-yl)cyclopropyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone(30 mg, 0.09 mmol) and O-ethyl-hydroxylamine hydrochloride (18 mg, 0.18mmol) in 2 mL of DCM was stirred at 40° C. overnight. The solvent wasremoved under reduced pressure and the residue was purified by flashchromatography on silica gel eluting with EtOAc/methanol gradient toafford the title compound. ¹H-NMR (400 MHz, CDCl₃) 3 ppm 8.84 (d, 1H),8.29 (d, 1H), 8.25 (d, 1H), 7.92-7.91 (m, 2H), 7.72-7.68 (m, 2H), 7.49(dd, 1H), 4.26 (q, 2H), 2.01 (s, 3H), 1.76 (s, 2H), 1.66 (s, 2H), 1.27(t, 3H). LCMS (method A): [MH]⁺=373, t_(R)=5.56 min.

Example 60(E)-1-(3-(1-(Quinolin-6-yl)cyclopropyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime

A solution of1-(3-(1-(quinolin-6-yl)cyclopropyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone(30 mg, 0.09 mmol) (59.4) and 2-aminooxy-ethanol hydrochloride(intermediate S) (14 mg, 0.18 mmol) in 4 mL of DCM and 0.5 mL of aceticacid was stirred at 40° C. overnight. The solvent was removed underreduced pressure and the residue was purified by flash chromatography onsilica gel eluting with a EtOAc/methanol gradient to afford the titlecompound. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.84 (t, 1H), 8.30 (d, 1H),8.25 (d, 1H), 7.93-7.91 (m, 2H), 7.71-7.68 (m, 2H), 7.51 (dd, 1H), 4.73(t, 1H), 4.23 (t, 2H), 3.65 (q, 2H), 2.02 (s, 3H), 1.78-1.75 (m, 2H),1.68-1.64 (m, 2H). LCMS (method A): [MH]⁺=389, t_(R)=4.55 min.

Example 61(E)-2-(1-(3-(Quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethylidene-aminooxy)acetamide

A microwave tube was charged with2-(1,3-dioxoisoindolin-2-yloxy)acetamide (intermediate V) (166 mg, 0.76mmol), hydrazine monohydrate (34.4 mg, 0.69 mmol) and 2 mL of methanol.It was heated at 95° C. for 12 h under microwave irradiation. Aftercooling, solid was removed by filtration and the solution wasconcentrated under reduced pressure. The residue was diluted withmethanol, then1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone(41.2) (32 mg, 0.105 mmol) and 0.3 mL of acetic acid were added and themixture was stirred at 40° C. overnight. After concentration, theresidue was purified by prep-HPLC to afford the title compound. ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 8.86 (dd, 1H), 8.33-8.27 (m, 2H), 7.98-7.95 (m,2H), 7.78 (dd, 1H), 7.69 (d, 1H), 7.50 (dd, 1H), 7.31 (d, 2H), 4.77 (s,2H), 4.63 (s, 2H), 2.32 (s, 3H). LCMS (method A): [MH]⁺=376, t_(R)=4.02min.

Example 62 Example 62-S and Example 62-R(E)-1-(3-(1-(7-Fluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime

2-(7-Fluoroquinolin-6-yl)propanehydrazide (62.1)

A solution of methyl 2-(7-fluoroquinolin-6-yl)propanoate (756 mg, 3.24mmol) and hydrazine monohydrate (1.5 mL) in methanol (5 mL) was heatedat 50° C. overnight. After cooling, the solvent was removed in vacuo toafford the title compound (756 mg, 100%) which was used without furtherpurification. LCMS (method A): [MH]⁺=234, t_(R)=3.14 min.

6-(1-(6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)-7-fluoroquinoline(62.2)

A sealed tube was charged with 2-(7-fluoroquinolin-6-yl)propanehydrazide(11.4 g, 48.9 mmol), 3,6-dichloro-pyridazine (8.01 g, 53.8 mmol) and 190mL of n-butanol. The mixture was heated at 140° C. for 12 h. Aftercooling, the solvent was removed in vacuo and the residue was purifiedby flash chromatography on silica gel eluting with EtOAc/methanolgradient to afford the title compound (7.1 g, 44%). ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.95 (d, 1H), 8.49-8.46 (m, 2H), 7.96 (d, 1H), 7.84 (d,1H), 7.58 (dd, 1H), 7.48 (dd, 1H), 5.17 (q, 1H), 1.88 (d, 3H). LCMS(method A): [MH]⁺=328, t_(R)=5.00 min.

1-(3-(1-(7-Fluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone(62.3)

A mixture of6-(1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)-7-fluoroquinoline(100 mg, 0.305 mmol), PdCl₂(PPh₃)₂ (21.4 mg, 0.031 mmol) andtributyl(1-ethoxyvinyl)stannane (220 mg, 0.61 mmol) in 5 mL of1,4-dioxane was heated at 90° C. for 5 h under nitrogen. The reactionmixture was diluted with EtOAc and washed with water. The organic layerwas dried over Na₂SO₄, filtered and concentrated in vacuo. The residuewas dissolved in HOAc and 3 N HCl, and stirred at rt for 3 h. Thesolvent was removed under reduced pressure and the residue was dissolvedin DCM, washed with saturated aqueous NaHCO₃ and brine. The organiclayer was dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel eluting withEtOAc/MeOH gradient to afford the title compound as a yellow solid.¹H-NMR (400 MHz, CDCl₃) δ ppm 8.87 (d, 1H), 8.16 (d, 1H), 8.03 (d, 1H),7.80 (d, 1H), 7.73 (d, 2H), 34 (dd, 1H), 5.39 (q, 1H), 2.62 (s, 3H),2.09 (d, 3H). LCMS (method A): [MH]⁺=336, t_(R)=4.95 min.

(E)-1-(3-(1-(7-Fluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime (Example 63, Example 62-S, Example 62-R)

The title compounds as a racemic mixture were prepared using the sameprocedure as described in the synthesis of example 53. Data for theracemic mixture example 63: ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.88 (d, 1H),8.11 (d, 1H), 8.00 (d, 1H), 7.86 (d, 1H), 7.75 (d, 2H), 7.38 (dd, 1H),5.36 (q, 1H), 4.38 (t, 2H), 3.93 (s, 3H), 2.24 (s, 3H), 2.06 (d, 3H).LCMS (method A): [MH]⁺=395, t_(R)=4.89 min.

The enantiomeric components of this racemic mixture were separated withmethod H: example 62-S, t_(R)=9.293 min and example 62-R, t_(R)=11.519min.

Example 63(E)-1-(3-((3-(4-Methylpiperazin-1-yl)quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime

Methyl 2-(3-(4-methylpiperazin-1-yl)quinolin-6-yl)acetate (63.1)

A solution of methyl 2-(3-bromoquinolin-6-yl)acetate (1.0 g, 3.57 mmol),1-methylpiperazine (0.429 g, 4.28 mmol), Pd₂(dba)₃ (65 mg, 0.071 mmol),BINAP (133 mg, 0.214 mmol) and Cs₂CO₃ (1.628 g, 5.00 mmol) in 10 mL oftoluene was heated at 100° C. for 18 h. After cooling, the solid wasremoved by filtration and the filtrate was concentrated under reducedpressure. The residue was purified by flash chromatography in silica geleluting with a EtOAC/hexane gradient to afford 599 mg (56%) of the titlecompound as a yellow solid. ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.77 (s, 1H),7.94 (d, 1H), 7.57 (s, 1H), 7.42 (d, 1H), 7.30 (s, 1H), 3.78 (s, 2H),3.72 (s, 3H), 3.41-3.33 (m, 4H), 2.65-2.63 (m, 4H), 2.39 (s, 3H). LCMS(method A): [MH]⁺=300, t_(R)=2.06 min.

2-(3-(4-Methylpiperazin-1-yl)quinolin-6-yl)acetohydrazide (63.2)

The title compound was prepared using the same procedure as described inthe synthesis of 53.2. LCMS (method A): [MH]⁺=300, t_(R)=1.30 min.

6-((6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-3-(4-methylpiperazin-1-yl)quinoline(63.3)

The title compound was prepared using the same procedure as described inthe synthesis of 53.3. ¹H-NMR (400 MHz, CDCl₃) 3 ppm 8.75 (d, 1H), 8.05(d, 1H), 7.92 (d, 1H), 7.68 (d, 1H), 7.56 (dd, 1H), 7.28 (s, 1H), 7.10(d, 1H), 4.70 (s, 2H), 3.33-3.30 (m, 4H), 2.65-2.63 (m, 4H), 2.39 (s,3H). LCMS (method A): [MH]⁺=394, t_(R)=2.679 min.

1-(3-((3-(4-Methylpiperazin-1-yl)quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone(63.4)

The title compound was prepared using the same procedure as described inthe synthesis of 53.4 and 53.5. LCMS (method A): [MH]⁺=402, t_(R)=2.506min.

(E)-1-(3-((3-(4-Methylpiperazin-1-yl)quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime (Example 63)

The title compound was prepared using the same procedure as described inthe synthesis of example 53. ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.74 (d, 1H),7.96 (d, 1H), 7.90 (d, 1H), 7.74 (d, 1H), 7.66 (s, 1H), 7.56 (dd, 1H),7.23 (d, 1H), 4.72 (s, 2H), 4.40 (t, 2H), 3.95 (t, 2H), 3.30 (t, 4H),2.63 (t, 4H), 2.38 (s, 3H), 2.32 (s, 3H). LCMS (method A): [MH]⁺=461,t_(R)=2.965 min.

Example 64(E)-1-(3-(1-(5,7-Difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-2-methoxyethyl oxime

A solution of(E)-1-(3-((5,7-difluoroquinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-2-hydroxyethyl oxime (31.0 mg, 0.078 mmol) (example 54), sodiumhydride (6.85 mg, 0171 mmol) and iodomethane (221 mg, 1.556 mmol) in 5mL of THF and 0.5 mL of DMF was stirred at it for 3 h. The reaction wasquenched by addition of 3 mL of methanol slowly. The solvent was removedunder reduced pressure and the residue was purified by flashchromatography on silica gel eluting with EtOAc/methanol gradient toafford the title compound. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.97 (dd,1H), 8.45 (dd, 1H), 8.26 (d, 1H), 7.70-7.65 (m, 2H), 7.60 (dd, 1H), 5.26(q, 1H), 4.30 (dd, 2H), 3.58 (dd, 2H), 3.23 (s, 3H), 2.02 (d, 3H), 1.88(s, 3H). LCMS (method A): [MH]⁺=427, t_(R)=5.50 min.

Example 65(E)-1-(3-((5,7-Difluoroquinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-4-hydroxybutyl oxime

The title compound was prepared using the same procedure as described inthe synthesis of example 53. ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.93 (dd,1H), 8.39-8.36 (m, 1H), 7.98 (d, 1H), 7.82 (d, 1H), 7.62 (d, 1H), 7.43(dd, 1H), 4.81 (s, 2H), 4.32 (t, 2H), 3.73-3.69 (m, 2H), 2.26 (s, 3H),1.88-1.81 (m, 2H), 1.73-1.66 (m, 2H). LCMS (method A): [MH]⁺=427,t_(R)=4.839 min.

Example 66(E)-1-(3-((5,7-Difluoroquinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-4-fluorobutyl oxime

To a solution of(E)-1-(3-((5,7-difluoroquinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-4-hydroxybutyl oxime (30 mg, 0.070 mmol) (example 65) in 4 mL of DCMat −78° C. was added bis(2-methoxyethyl)aminosulfur trifluoride (180 mg,0.813 mmol). The mixture was stirred at this temperature for 1 h, andstirred at it overnight. The mixture was poured into saturated aqueousNaHCO₃, extracted with DCM, dried over Na₂SO₄, filtered and concentratedin vacuo. Flash chromatography on silica gel eluting with DCM/methanolafforded the title compound. ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.94 (s, 1H),8.37 (d, 1H), 7.98 (d, 1H), 7.81 (d, 1H), 7.63 (d, 1H), 7.44 (dd, 1H),4.81 (s, 2H), 4.58-4.57 (m, 1H), 4.45 (t, 1H), 4.32 (t, 2H), 2.26 (s,3H), 1.90-1.78 (m, 4H). LCMS (method A): [MH]⁺=429, t_(R)=5.239 min.

Example 67(E)-1-(6-((6-((E)-1-(2-Hydroxyethoxyimino)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinolin-3-yl)ethanoneO-2-hydroxyethyl oxime

(3-Bromo-quinolin-6-yl)-methanol (67.1)

To a stirred solution of methyl 3-bromo-quinoline-6-carboxylate (1.09 g,4 mmol) in THF (50 mL) at 0° C. was added LiAlH₄ (0.155 g, 4 mmol) insmall portions. The resulting mixture was stirred at 0° C. for 0.5 h.Water (0.2 mL) was added dropwise, followed by 0.2 mL of 10% aq. NaOHand 0.2 mL of water. The solid was removed and the solvent wasconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with EtOAc/hexane gradient to afford the titlecompound (413 mg, 42%). LCMS (method A): [MH]⁺=238/240, t_(R)=4.453 min.

2-(3-Bromo-quinolin-6-ylmethyl)-isoindole-1,3-dione (67.2)

To a solution of phthalimide (281 mg, 1.9 mmol), triphenyl phosphine(500 mg, 1.9 mmol) in 10 mL of THF was added DIAD (386 mg, 1.9 mmol)dropwise at 0° C. and the mixture was stirred at this temperature for 10min. (3-Bromo-quinolin-6-yl)-methanol (413 mg, 1.7 mmol) was added tothe above solution in one portion and the resulting solution was stirredat rt for 30 min, then heated at 40° C. for 5 h. After cooling, thereaction mixture was taken up with EtOAc, washed with water, extractedwith EtOAc. The organic layer was dried over Na₂SO₄, filtered,concentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with EtOAc/hexane gradient to afford the titlecompound. ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.89 (d, 1H), 8.31 (d, 1H), 8.06(d, 1H), 7.90-7.86 (m, 3H), 7.82-7.73 (m, 3H), 5.04 (s, 2H). LCMS(method A): [MH]⁺=368/370, t_(R)=5.54 min.

(3-Bromoquinolin-6-yl)methanamine (67.3)

A solution of 2-(3-Bromo-quinolin-6-ylmethyl)-isoindole-1,3-dione (635g, 1.73 mmol) in 15 mL of methanol and 1 mL of hydrazine monohydrate washeated at 80° C. for 2 h. After cooling, the solvent was removed invacuo and the residue was purified by flash chromatography on silica geleluting with EtOAc/methanol gradient to afford the title compound. LCMS(method A): [MH]⁺=237/239, t_(R)=2.795 min.

6-Bromo-N2-((3-bromoquinolin-6-yl)methyl)pyrazine-2,3-diamine (67.4)

A microwave tube was charged with (3-bromoquinolin-6-yl)methanamine (237mg, 1.0 mmol), 3,5-dibromopyrazin-2-amine (253 mg, 1.0 mmol), DIPEA (0.6mL) and 5 mL of ethanol. The tube was heated at 120° C. under microwaveirradiation for 15 h. After cooling, the solvent was removed underreduced pressure and the residue was purified by flash chromatography onsilica gel eluting with DCM/methanol gradient to afford the titlecompound. LCMS (method E): [MH]⁺=406/408/410, t_(R)=5.803 min.

3-Bromo-6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline(67.5)

To a solution of6-bromo-N2-((3-bromoquinolin-6-yl)methyl)pyrazine-2,3-diamine (300 mg,0.73 mmol) in 5 mL of acetic acid was added dropwise a solution of NaNO₂(150 mg, 2.17 mmol) in 0.5 mL of water at 20° C. The mixture was stirredat rt overnight. The solvent was removed under reduced pressure and theresidue was purified by flash chromatography on silica gel eluting withDCM/methanol gradient to afford the title compound (130 mg, 42%). ¹H-NMR(400 MHz, CDCl₃) δ ppm 8.84 (s, 1H), 8.71 (s, 1H), 8.24 (s, 1H), 8.01(d, 1H), 7.74 (s, 2H), 5.99 (s, 2H). LCMS (method E): [MH]⁺=421,t_(R)=5.50 min.

1-(6-((6-Acetyl-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinolin-3-yl)ethanone(67.6)

A solution of3-bromo-6-β6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline(128 mg, 0.305 mmol), Pd(PPh₃)₄ (51.5 mg, 0.045 mmol) andtributyl(1-ethoxyvinyl)stannane (253 mg, 0.701 mmol) in 5 mL of DMF washeated at 95° C. for 1 h under nitrogen. The reaction mixture wasdiluted with EtOAc, washed with water. The organic layer was separated,dried over Na₂SO₄, filtered and concentrated in vacuo. The residue wasdissolved in HOAc and 3 N HCl, and stirred at rt for 3 h. The solventwas removed under reduced pressure and the residue was dissolved in DCM,washed with saturated aqueous NaHCO₃ and brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by flash chromatography on silica gel eluting with DCM/MeOHgradient to afford the title compound (74 mg, 45%) as a yellow solid.¹H-NMR (400 MHz, CDCl₃) δ ppm 9.47-9.45 (m, 2H), 8.70 (d, 1H), 8.19 (d,1H), 8.05 (d, 1H), 7.97 (dd, 1H), 6.21 (s, 2H), 2.82 (s, 3H), 2.74 (s,3H). LCMS (method E): [MH]⁺=347, t_(R)=4.503 min.

(E)-1-(6-((6-((E)-1-(2-Hydroxyethoxyimino)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinolin-3-yl)ethanoneO-2-hydroxyethyl oxime (example 67)

A solution of1-(6-β6-acetyl-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinolin-3-yl)ethanone(74 mg, 0.213 mmol) and 2-aminooxy-ethanol (35 mg, 0.45 mmol) in 5 mL ofmethanol and 0.1 mL of acetic acid was stirred at 40° C. overnight. Thesolvent was removed under reduced pressure and the residue was dilutedwith DCM and methanol. The precipitate was collected, washed with DCM,dried to afford the title compound (16 mg, 15%) as a white solid. ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 9.31 (s, 1H), 9.23 (d, 1H), 8.52 (d, 1H), 8.03(d, 1H), 7.98 (s, 1H), 7.86 (dd, 1H), 6.22 (s, 2H), 4.76 (d, 2H), 4.31(t, 2H), 4.22 (t, 2H), 3.72-3.69 (m, 4H), 2.32 (s, 3H), 2.29 (s, 3H).LCMS (method E): [MH]⁺=465, t_(R)=4.85 min.

Example 68 Example 68-R, Example 68-S(E)-2-(1-(3-(1-(5,7-Difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethylideneaminooxy)aceticacid

Methyl 2-(1,3-dioxoisoindolin-2-yloxy)acetate (237 mg, 1.01 mmol) andhydrazine monohydrate (50 mg, 1.0 mmol) were dissolved in methanol (3mL) and heated at 70° C. for 2 h. After filtration, the solid was washedwith EtOAc. The combined solution was concentrated and the residue wasdiluted with methanol. A solution of NaOH (6 N, 3 mL) was added and themixture was stirred at 70° C. for 2 h. The solution was concentrated,acidified with 3 N HCl to pH 1 and filtered. The solid was washed withwater, and the combined solution was concentrated. The residue wasdiluted with DCM, then ketone 53.5 (40 mg, 0.113 mmol) and HCl (4 N HClin dioxane, 0.7 mL) were added. It was stirred at rt for 24 h. Afterconcentration, the residue was purified by prep-HPLC to give 21 mg (34%)of the title compound as white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm12.90 (s, 1H), 8.97 (d, 1H), 8.45 (d, 1H), 8.26 (d, 1H), 7.70 (d, 1H),7.60 (d, 1H), 5.27 (q, 1H), 4.76 (s, 2H), 2.03 (d, 3H), 1.94 (s, 3H).LCMS (method B): [MH]⁺=427, t_(R)=2.259 min. Chiral separation (methodL) provided enantiomeric pure compounds example 68-R (t_(R)=7.71 min)and example 68-S (t_(R)=9.99 min).

Example 69(E)-1-(1-((5,7-Difluoroquinolin-6-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-2-hydroxyethyl oxime

(5,7-Difluoroquinolin-6-yl)methanol (69.1)

To a solution of 5,7-difluoroquinoline-6-carbaldehyde (4.00 g, 20.71mmol) in MeOH (120 mL), was added NaBH₄ (0.79 g, 20.71 mmol) inportions. After stirring for 15 min, saturated aqueous solution of NH₄Clwas added. The aqueous phase was extracted with CH₂Cl₂ (4×25 mL). Theorganic layers were combined and dried over NaSO₄. The product waspurified by silica gel with hexane:EtOAc to afford(5,7-difluoroquinolin-6-yl)methanol (3.80 g, 94%). ¹H-NMR (400 MHz,CDCl₃) δ ppm 8.97 (m, 1H), 8.42 (m, 1H), 7.63 (d, 1H), 7.46 (m, 1H),4.99 (d, 2H), 2.07 (t, 1H). LCMS (method B): [MH]⁺=196.0, t_(R)=1.67 min

2-(5,7-Difluoroquinolin-6-ylmethyl)isoindoline-1,3-dione (69.2)

A mixture of (E)-diisopropyl diazene-1,2-dicarboxylate (4.72 g, 23.36mmol) and triphenylphosphine (6.13 g, 23.36 mmol) in THF (100 mL) wasstirred for 15 min, and a solution of(5,7-difluoroquinolin-6-yl)methanol (3.80 g, 19.47 mmol) andisoindoline-1,3-dione (3.15 g, 21.42 mmol) in THF (200 mL) was addeddropwise. The reaction mixture was heated at 40° C. for 24 h. Aftercooling and evaporating, the residue was purified by silica gel withhexane:EtOAc to provide2-(5,7-difluoroquinolin-6-ylmethyl)isoindoline-1,3-dione (5.10 g, 81%).¹H-NMR (400 MHz, CDCl₃) δ ppm 8.93 (m, 1H), 8.39 (m, 1H), 7.85 (m, 2H),7.72 (m, 2H), 7.59 (d, 1H), 7.43 (m, 1H), 5.15 (s, 2H).

(5,7-Difluoroquinolin-6-yl)methanamine (69.3)

To a solution of2-(5,7-difluoroquinolin-6-ylmethyl)isoindoline-1,3-dione (5.10 g, 15.73mmol) in CH₃OH (150 mL) was added hydrazine monohydrate (0.50 g, 15.73mmol). The solution was heated at reflux for 3 h. After cooling, themixture was filtered through celite. The filtrate was concentrated invacuo. EtOAc was added to dilute the residue, filtered and concentratedin vacuo to afford (5,7-difluoroquinolin-6-yl)methanamine (2.70 g, 88%).¹H-NMR (400 MHz, CDCl₃) δ ppm 8.93 (d, 1H), 8.38 (d, 1H), 7.59 (d, 1H),7.43 (m, 1H), 4.12 (s, 2H). LCMS (method B): [MH]⁺=195.0, t_(R)=0.17min.

6-Bromo-N2-(5,7-difluoroquinolin-6-ylmethyl)pyrazine-2,3-diamine (69.4)

A mixture of (5,7-difluoroquinolin-6-yl)methanamine (2.7 g, 13.9 mmol),3,5-dibromopyrazin-2-amine (2.4 mg, 9.49 mmol) and triethyl amine (4.8g, 47.5 mmol) in CH₃CN (6 mL) was heated under microwave irradiation at180° C. for 40 min. The reaction mixture was concentrated in vacuo andpurified by column chromatography (hexane:EtOAc) to provide6-bromo-N2-(5,7-difluoroquinolin-6-ylmethyl)pyrazine-2,3-diamine (1.50g, 43%). ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.00 (d, 1H), 8.52 (d, 1H),7.73 (d, 1H), 7.64 (m, 1H), 7.21 (s, 1H), 7.00 (s, 1H), 6.21 (s, 2H),4.69 (d, 2H). LCMS (method B): [MH]⁺=367.9, t_(R)=2.36 min

6-((6-Bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-5,7-difluoroquinoline(69.5)

To a solution of6-bromo-N2-(5,7-difluoroquinolin-6-ylmethyl)pyrazine-2,3-diamine (1.5 g,4.10 mmol) in acetic acid (50 mL) and water (10 mL) was added a solutionof sodium nitrite (283 mg, 4.10 mmol) in water (3 mL). After stirring atit for 3 h, the solvent was removed in vacuo, the residue was taken withNaHCO₃ (aq.), extracted with CH₂Cl₂. The organic layer was washed withNH₄Cl (aq.), dried over Na₂SO₄, filtered and concentrated in vacuo andpurified by silica gel chromatography with hexanes:EtOAc to provide6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-5,7-difluoroquinoline(1.02 g, 65%). ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.99 (d, 1H), 8.79 (s, 1H),8.43 (d, 1H), 7.65 (d, 1H), 7.49 (m, 1H), 6.13 (s, 2H). LCMS (method B):[MH]⁺=376.8, t_(R)=2.23 min.

6-((6-(1-Ethoxyvinyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-5,7-difluoroquinoline(69.6)

To a degassed solution of6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-5,7-difluoroquinoline(10 mg, 0.03 mmol) in DMF (1 mL) was added Pd(Ph₃P)₄ (3.1 mg, 2.65μmol). After stirring for 20 min, tributyl(1-ethoxyvinyl)stannane (14.4mg, 0.04 mmol) was added. The reaction was heated at 100° C. until theLC-MS showed its completetion. The reaction mixture was filtered throughcelite and washed with ether. The filtration was washed with water,dried over Na₂SO₄, and concentrated. The crude product was purified bycolumn chromatography with hexane:EtOAc to give6-((6-(1-ethoxyvinyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-5,7-difluoroquinoline(6.0 mg, 61%). ¹H-NMR (400 MHz, CDCl₃) δ ppm 9.16 (s, 1H), 8.98 (d, 1H),8.43 (d, 1H), 7.65 (d, 1H), 7.48 (m, 1H), 6.17 (s, 2H), 5.60 (s, 1H),4.57 (s, 1H), 4.04 (q, 2H), 1.49 (t, 3H). LCMS (method B): [MH]⁺=369.0,t_(R)=2.45 min.

1-(1-((5,7-Difluoroquinolin-6-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone(69.7)

To a solution of the6-((6-(1-ethoxyvinyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-5,7-difluoroquinoline(6.0 mg, 0.45 mmol) in acetic acid, 3N HCl (0.1 mL) was added. Thesolution stirred at it for 2 h. Solvents were removed under reducedpressure. The residue was diluted with water, treated with aqueousNaHCO₃ solution, extracted with DCM. The organic layer was washedsequencially with NaHCO₃ (aq.) and brine, dried over Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by silica gel columnchromatography with Hexane:ethyl acetate to give yellow solid1-(1-((5,7-difluoroquinolin-6-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone(3.5 mg), yield 63%. LCMS (method B): [MH]⁺=340.9, t_(R)=2.09 min.

(E)-1-(1-((5,7-Difluoroquinolin-6-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-2-hydroxyethyl oxime (Example 69)

To a solution of1-(1-((5,7-difluoroquinolin-6-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone(3.5 mg, 0.01 mmol) in MeOH (1 mL), 2-(aminooxy)ethanol hydrochloride(intermediate S) (1.6 mg, 0.02 mmol) was added, the solution was heatedto 50° C. for overnight. The solvent was removed in vacuo. The residuewas diluted with water, treated with aqueous NaHCO₃ solution, extractedwith DCM. The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by prepared HPLCto give white solid(E)-1-(14(5,7-difluoroquinolin-6-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-2-hydroxyethyl oxime (2.4 mg, 56%). ¹H-NMR (400 MHz, CDCl₃) δ ppm 9.38(s, 1H), 8.98 (d, 1H), 8.42 (d, 1H), 7.64 (d, 1H), 7.48 (m, 1H), 6.18(s, 2H), 4.45 (m, 2H), 3.98 (m, 2H), 2.36 (s, 3H), 1.96 (m, 1H). LCMS(method B): [MH]⁺=399.9, t_(R)=2.19 min.

Example 70(E)-1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-1-hydroxy-2-methylpropan-2-yl oxime

The title compound was prepared from1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone(22.4) and 2-(aminooxy)-2-methylpropan-1-ol hydrochloride in 94% yieldusing the same procedure as described in the synthesis of example 22.¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.35 (s, 1H), 8.89 (m, 1H), 8.35 (dd,1H), 8.01 (m, 2H), 7.82 (m, 1H), 7.52 (dd, 1H), 6.20 (s, 2H), 4.73 (t,1H), 3.51 (d, 2H), 2.29 (s, 3H), 1.13 (s, 6H). LCMS (method B):[MH]⁺=392, t_(R)=2.40 min.

Example 71(E)-1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-oxetan-3-yl oxime

The title compound was prepared from1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone(22.4) and O-(oxetan-3-yl)hydroxylamine (intermediate U) in 23% yieldusing the same procedure as described in the synthesis of example 22.¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.27 (s, 1H), 8.89 (m, 1H), 8.35 (d,1H), 8.01 (m, 2H), 7.82 (m, 1H), 7.52 (dd, 1H), 6.22 (s, 2H), 5.45 (t,1H), 4.86 (t, 2H), 4.66 (m, 2H), 2.40 (s, 3H). LCMS (method B):[MH]⁺=376, t_(R)=2.26 min.

Example 72(E)-1-(1-((7-Fluoroquinolin-6-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneoxime

The title compound (68.0 mg, 62%) was synthesized from1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone(15.4) (100.0 mg, 0.31 mmol) and hydroxylamine hydrochloride (43.1 mg,0.62 mmol) using the same procedure as described in the synthesis ofexample 15. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 12.49 (bs, 1H), 9.31 (s,1H), 8.92 (d, 1H), 8.40 (d, 1H), 8.18 (d, 1H), 7.82 (d, 1H), 7.54 (d,1H), 6.22 (s, 2H), 2.23 (s, 3H). LCMS (method A): [MH]⁺=338, t_(R)=5.15min.

Example 73(E)-1-(1-(1-(5,7-Difluoroquinolin-6-yl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-2-hydroxyethyl oxime

1-(5,7-Difluoroquinolin-6-yl)ethanol (73.1)

To a solution of 5,7-difluoroquinoline-6-carbaldehyde (5.0 g, 25.9 mmol)in THF (80 mL) was added ethylmagnesium iodide (3 M, 9.5 mL, 28.5 mmol)at −78° C. After stirring at −78° C. for 1 hour, the reaction wasquenched with saturated NH₄Cl and concentrated under reduced pressure.The residue was diluted with water, extracted with DCM three times. Theorganic layers were combined, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product was purified bychromatography (hexane/EtOAc) to give the title compound as a whitesolid (3.3 g, 58%). ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.97 (dd, 1H), 8.47(d, 1H), 7.66-7.58 (m, 2H), 5.54 (d, 1H), 5.29 (m, 1H), 1.56 (d, 3H).LCMS (method A): [MH]⁺=210, t_(R)=4.71 min.

2-(1-(5,7-Difluoroquinolin-6-yl)ethyl)isoindoline-1,3-dione (73.2)

A mixture of (E)-diisopropyl diazene-1,2-dicarboxylate (3.8 g, 18.9mmol) and triphenylphosphine (5.4 g, 20.5 mmol) in THF (50 mL) wasstirred for 30 min, and a solution of1-(5,7-difluoroquinolin-6-yl)ethanol (3.3 g, 15.8 mmol) andisoindoline-1,3-dione (2.7 g, 17.4 mmol) in THF (50 mL) was addeddropwise. The reaction mixture was heated at 50° C. overnight. Aftercooling and evaporating, the residue was purified by silica gel andeluted with hexane/EtOAc to give the title compound as a white solid(2.6 g, 49%). LCMS (method A): [MH]⁺=339, t_(R)=5.81 min.

1-(5,7-Difluoroquinolin-6-yl)ethanamine (73.3)

To a solution of2-(1-(5,7-difluoroquinolin-6-yl)ethyl)isoindoline-1,3-dione (2.6 g, 7.7mmol) in CH₃OH (50 mL) was added hydrazine monohydrate (0.38 g, 7.7mmol). The solution was heated at 50° C. and stirred overnight. Aftercooling and evaporating, the residue was purified by silica gel andeluted with hexane/EtOAc to give the title compound (1.0 g, 60%). ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 8.95 (d, 1H), 8.45 (d, 1H), 7.65 (d, 1H), 7.60(dd, 1H), 4.49 (q, 1H), 2.20 (bs, 2H), 1.48 (d, 3H).

6-Bromo-N2-(1-(5,7-difluoroquinolin-6-yl)ethyl)pyrazine-2,3-diamine(73.4)

A mixture of 1-(5,7-difluoroquinolin-6-yl)ethanamine (800 mg, 3.8 mmol),3,5-dibromopyrazin-2-amine (972.0 mg, 3.8 mmol) and DIPEA (2.0 g, 15.4mmol) in acetonitrile (50 mL) was heated with microwave irradiation at180° C. for 45 min. The reaction mixture was concentrated under reducedpressure, diluted with water, extracted with DCM three times. Thecombined organic layers were separated and washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by silica gel chromatography (DCM/MeOH) to give the titlecompound as a yellow solid (508 mg, 35%). ¹H-NMR (400 MHz, DMSO-d₆) δppm 8.95 (d, 1H), 8.46 (dd, 1H), 7.63 (d, 1H), 7.60 (dd, 1H), 7.11 (s,1H), 7.08 (dd, 1H), 6.36 (bs, 2H), 5.45 (m, 1H), 1.70 (d, 3H). LCMS(method A): [MH]⁺=380/382, t_(R)=5.03 min.

6-(1-(6-Bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)ethyl)-5,7-difluoroquinoline(73.5)

To a solution of6-bromo-N2-(1-(5,7-difluoroquinolin-6-yl)ethyl)pyrazine-2,3-diamine (450mg, 1.2 mmol) in acetic acid (12 mL) was added a solution of sodiumnitrite (82.0 mg, 1.2 mmol) in water (2 mL). After stirring at rt for 2hours, the solvent was removed in vacuo. The residue was diluted withNaHCO₃ (aq.), extracted with DCM. The organic layer was separated andwashed with water, dried over Na₂SO₄, filtered and concentrated in vacuoto give the title compound as a yellow solid (423 mg, 91%). ¹H-NMR (400MHz, DMSO-d₆) δ ppm 9.01 (dd, 1H), 8.95 (s, 1H), 8.52 (d, 1H), 7.75 (d,1H), 7.64 (dd, 1H), 6.77 (q, 1H), 2.30 (d, 3H). LCMS (method A):[MH]⁺=391/393, t_(R)=5.59 min.

6-(1-(6-(1-Ethoxyvinyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)ethyl)-5,7-difluoroquinoline(73.6)

A mixture of6-(1-(6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)ethyl)-5,7-difluoroquinoline(423.0 mg, 1.2 mmol), Pd(Ph₃P)₄ (125.0 mg, 0.12 mmol) andtributyl(1-ethoxyvinyl)stannane (781.0 mg, 2.2 mmol) in DMF (5 mL) waspurged with nitrogen and then heated at 100° C. for 12 hours. Afterremoval of the solvent under reduced pressure, the residue was dilutedwith DCM, washed sequentially with aqueous KF and water, dried overNa₂SO₄ and concentrated in vacuo. The crude product was purified bycolumn chromatography on silica gel with gradient (DCM/MeOH=50:1) togive the title compound as a yellow solid (370 mg, 91%). LCMS (methodE): [MH]⁺=383, t_(R)=4.24 min.

1-(1-(1-(5,7-Difluoroquinolin-6-yl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone(73.7)

A solution of6-(1-(6-(1-ethoxyvinyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)ethyl)-5,7-difluoroquinoline(100.0 mg, 0.24 mmol) and 3 N HCl (0.1 mL) in CH₃OH (10 mL) was stirredat 50° C. for 2 hours. The solvent was removed under reduced pressure.The reaction mixture was concentrated in vacuo to give the titlecompound as yellow solid (80.0 mg, 96%). ¹H-NMR (400 MHz, DMSO-d₆) δ ppm9.23 (s, 1H), 9.01 (dd, 1H), 8.53 (d, 2H), 7.76 (d, 1H), 7.64 (dd, 1H),6.87 (q, 1H), 2.49 (s, 3H), 2.40 (d, 3H). LCMS (method A): [MH]⁺=355,t_(R)=5.36 min.

(E)-1-(1-(1-(5,7-Difluoroquinolin-6-yl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-2-hydroxyethyl oxime (example 73)

To a solution of1-(1-(1-(5,7-difluoroquinolin-6-yl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone(76.5 mg, 0.22 mmol) in MeOH (50 mL) was added 2-(aminooxy)ethanolhydrochloride (49.0 mg, 0.43 mol). The mixture was heated at 45° C.overnight. The solvent was removed under reduced pressure. The residuewas purified by column chromatography with gradient (DCM/MeOH=10:1) togive the title compound as a white solid (58.0 mg, 62%). ¹H-NMR (400MHz, DMSO-d₆) δ ppm 9.23 (s, 1H), 9.01 (dd, 1H), 8.52 (d, 1H), 7.74 (d,1H), 7.63 (dd, 1H), 6.80 (q, 1H), 4.74 (t, 1H), 4.27 (t, 2H), 3.68 (m,2H), 2.36 (d, 3H), 2.10 (s, 3H). LCMS (method A): [MH]⁺=414, t_(R)=5.44min.

Example 74(E)-1-(1-(1-(5,7-Difluoroquinolin-6-yl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneoxime

The title compound (26.4 mg, 63%) was synthesized from1-(1-(1-(5,7-difluoroquinolin-6-yl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone(73.7) (40.0 mg, 0.11 mmol) and hydroxylamine hydrochloride (15.7 mg,0.23 mmol) using the same procedure as described in the synthesis ofexample 73. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 12.28 (bs, 1H), 9.23 (s,1H), 9.01 (d, 1H), 8.52 (d, 1H), 7.73 (d, 1H), 7.63 (dd, 1H), 6.80 (q,1H), 2.36 (d, 3H), 2.05 (s, 3H). LCMS (method A): [MH]⁺=370, t_(R)=5.53min.

Example 75-S and 75-R (S,E)- and(R,E)-1-(3-(1-(5,7-difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneoxime

(E)-1-(3-(1-(5,7-Difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneoxime (example 75)

1-(3-(1-(5,7-difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone(53.5, 491 mg, 1.390 mmol) in methanol (30 mL) was added hydroxylaminehydrochloride (140 mg, 2.015 mmol), followed by hydrochloride dropwiseto give a pale yellow clear solution. The reaction mixture was stirredat it overnight. LCMS showed the reaction was complete. Aqueous NaOH(1N) solution was added at 0° C. until pH 8-9. Solvent was evaporated,and the residue was purified by column chromatography to afford 410 mg(88% yield) of the title compound as a white solid. ¹H-NMR (400 MHz,DMSO-d₆) 3 ppm 12.21 (s, 1H), 8.97 (dd, 1H), 8.45 (d, 1H), 8.22 (d, 1H),7.57-7.71 (m, 3H), 5.25 (q, 1H), 2.01 (d, 3H), 1.84 (s, 3H). LCMS(method A): [MH]⁺=369, t_(R)=5.45 min.

(S,E)- and(R,E)-1-(3-(1-(5,7-Difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneoxime (Example 75-S and 75-R)

The title compounds were obtained by separation of racemic mixture(E)-1-(3-(1-(5,7-difluoroquinolin-6-yl)ethyl)-[1,2,4]-triazolo[4,3-b]pyridazin-6-yl)ethanoneoxime (75, 12.0 g) with SFC (Method L). Data for example 75-S (4.98 g):¹H-NMR (400 MHz, DMSO-d₆) δ ppm 12.20 (s, 1H), 8.96 (d, 1H), 8.44 (d,1H), 8.22 (d, 1H), 7.56-7.70 (m, 3H), 5.25 (q, 1H), 2.01 (d, 3H), 1.84(s, 3H). LCMS (method B): [MH]⁺=369, t_(R)=2.35 min. Data for example75-R (5.08 g): ¹H-NMR (400 MHz, DMSO-d₆) 3 ppm 12.20 (s, 1H), 8.96 (d,1H), 8.44 (d, 1H), 8.22 (d, 1H), 7.56-7.70 (m, 3H), 5.25 (q, 1H), 2.01(d, 3H), 1.84 (s, 3H). LCMS (method B): [MH]⁺=369, t_(R)=2.35 min.

Example 76-S and 76-R (S,E)- and(R,E)-1-(3-(1-(5,7-Difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-cyclopropylmethyl oxime

(E)-1-(3-(1-(5,7-Difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-cyclopropylmethyl oxime (example 76)

2-(cyclopropylmethoxy)isoindoline-1,3-dione (300 mg, 1.42 mmol), andhydrazine monohydrate (35 μL, 0.71 mmol) in methanol (5 mL) was heatedat 75° C. for 3 hr. The reaction mixture was cooled, and the precipitatewas filtered off, and washed twice with minimum methanol. To thecombined methanol solution was added1-(3-(1-(5,7-difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone(53.6, 100 mg, 0.28 mmol), followed by hydrochloride (1N in dioxane)dropwise to give a clear solution. The reaction mixture was stirred atrt overnight, LCMS showed the reaction was complete. 1N NaOH aqueoussolution was added until pH 8-9. The mixture was concentrated, andpurified by column chromatography to afford 109 mg (91% yield) of thetitle compound as a white solid. ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.93 (dd,1H), 8.33 (d, 1H), 7.96 (d, 1H), 7.75 (d, 1H), 7.59 (d, 1H), 7.41 (dd,1H), 5.28 (q, 1H), 4.03 (d, 2H), 2.19 (d, 3H), 2.02 (s, 3H), 1.13-1.22(m, 1H), 0.52-0.62 (m, 2H), 0.22-0.31 (m, 2H). LCMS (method A):[MH]⁺=423, t_(R)=5.49 min.

(S,E)- and(R,E)-1-(3-(1-(5,7-Difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-cyclopropylmethyl oxime (example 76-S and 76-R)

The title compounds were obtained by separation of racemic mixture(E)-1-(3-(1-(5,7-difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-cyclopropylmethyl oxime (76, 102 mg) with SFC (Method I). Data forexample 76-S (32 mg): ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.96 (dd, 1H),8.44 (d, 1H), 8.24 (d, 1H), 7.66 (dd, 2H), 7.9 (dd, 1H), 5.25 (q, 1H),4.01 (d, 2H), 2.02 (d, 3H), 1.89 (s, 3H), 1.04-1.18 (m, 1H), 0.45-0.56(m, 2H), 0.26-0.31 (m, 2H). Data for example 76-R (42 mg): ¹H-NMR (400MHz, DMSO-d₆) δ ppm 8.96 (dd, 1H), 8.44 (d, 1H), 8.24 (d, 1H), 7.66 (dd,2H), 7.9 (dd, 1H), 5.25 (q, 1H), 4.01 (d, 2H), 2.02 (d, 3H), 1.89 (s,3H), 1.04-1.18 (m, 1H), 0.45-0.56 (m, 2H), 0.26-0.31 (m, 2H).

Example 77-R(R,E)-1-(3-(1-(5,7-difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-carbamoyl oxime

Previously prepared(E)-1-(3-(1-(5,7-difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneoxime (75-R, 100 mg, 0.271 mmol) in anhydrous THF (8 mL) was addeddiphosgene (0.1 mL, 0.829 mmol) dropwise at 0° C., and the reactionmixture was heated at 50° C. for 4 hr. Oil bath was removed, and thereaction mixture was cooled in an ice-water bath. An ammonia solution(0.5 N in dioxane, 8.0 mL, 4.0 mmol) was added dropwise. The temperaturewas allowed to rise to rt naturally, and the reaction mixture wasstirred at rt overnight. Solvent was evaporated, and the residue waspurified by column chromatography (8% methanol in ethyl acetate aseluent) to afford 64 mg (45.8% yield) of title compound as white solid,which was unstable at nucleophiles such as methanol, and was pro todegrade into starting material 75-R. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm8.96 (d, 1H), 8.44 (d, 1H), 8.34 (d, 1H), 8.10 (d, 1H), 7.56-7.74 (m,2H), 7.34 (s br, 2H), 5.27 (q, 1H), 2.02 (d, 3H), 2.03 (s, 3H). LCMS(method B): [MH]⁺=412, t_(R)=2.25 min.

Example 77-S(S,E)-1-(3-(1-(5,7-difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneO-carbamoyl oxime

The title compounds were obtained from(E)-1-(3-(1-(5,7-difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneoxime (75-S) with similar procedure as example 77-R. ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.96 (d, 1H), 8.44 (d, 1H), 8.34 (d, 1H), 8.10 (d, 1H),7.56-7.74 (m, 2H), 7.34 (s br, 2H), 5.27 (q, 1H), 2.02 (d, 3H), 2.03 (s,3H). LCMS (method B): [MH]⁺=412, t_(R)=2.20 min.

Example 78(E)-1-(3-((5,7-Difluoroquinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneoxime

(5,7-Difluoro-quinolin-6-yl)-acetic acid hydrazide (78.1)

To a solution of (5,7-difluoro-quinolin-6-yl)-acetic acid methyl ester(1.023 g, 4.32 mmol) in ethanol (15 mL) was added hydrazine monohydrate(2 mL) and the mixture was stirred at 30° C. for 24 h. The solvent wasremoved in vacuo to afford 1.024 g of the title compound as white solid,which was used without further purification. ¹H-NMR (400 MHz, DMSO-d₆) δppm 9.33 (s, 1H), 8.97 (d, 1H), 8.46 (d, 1H), 7.67 (d, 1H), 7.61 (dd,1H), 4.27 (s, 2H). LCMS (method A): [MH]⁺=238, t_(R)=3.24 min.(5,7-difluoroquinolin-6-yl)-acetic acid methyl ester was synthesizedusing the method described in WO2008/144767 p 108 (intermediate 2),followed by the method described for Intermediate 12, step 1WO2008/144767 p 114.

6-(6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-5,7-difluoro-quinoline(78.2)

A solution of (5,7-difluoro-quinolin-6-yl)-acetic acid hydrazide (1.024g, 4.32 mmol) and 3,6-dichloropyridazine (0.772 g, 5.18 mmol) in 60 mLof butan-1-ol was heated at 135° C. in a sealed tube for 16 h. Thesolvent was removed in vacuo, and the residue was purified by flashchromatography to afford 842 mg of the title compound as a gray solid.¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.96 (dd, 1H), 8.26 (d, 1H), 7.60-7.66(m, 2H), 7.45 (d, 1H), 4.81 (s, 2H). LCMS (method A): [MH]⁺=332,t_(R)=4.88 min.

6-[6-O-Ethoxy-vinyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl]-5,7-difluoro-quinoline(78.3)

A solution of6-(6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-5,7-difluoro-quinoline(58 mg, 0.175 mmol) in dioxane (5 mL) was purged with argon for 1 min.Tributyl-(1-ethoxy-vinyl)stannane (0.2 mL, 0.53 mmol) was then added,followed by addition of PdCl₂(PPh₃)₂ (14.4 mg, 0.021 mmol). The reactionmixture was purged with argon for another half min. The reaction mixturewas stirred at 80-85° C. for 4 h; LC/MS showed the reaction wascomplete. The reaction mixture was diluted with EtOAc, and 15 mL ofaqueous KF solution was added. The mixture was extracted with EtOAc,dried over anhydrous Na₂SO₄, concentrated to give the crude titlecompound, which was used without further purification. LCMS (method A):[MH]⁺=368, t_(R)=5.39 min.

1-[3-(5,7-Difluoro-quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]ethanone(78.4)

Aqueous 3N HCl (0.2 mL, 0.6 mmol) was added to a solution of6-[6-(1-ethoxy-vinyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl]-5,7-difluoro-quinoline(87 mg, 0.237 mmol) in HOAc (2 mL). The reaction mixture was stirred at40° C. for 6 h. LC/MS showed reaction was complete. The solvent wasremoved in vacuo, and the residue dissolved in EtOAc was neutralized,and extracted with EtOAc. The organic layer was dried, concentrated andpurified by flash chromatography to afford 40 mg of the title compoundas a pale yellow solid. ¹H-NMR (400 MHz, MeOH-d₄) δ ppm 8.95 (dd, 1H),8.56 (d, 1H), 8.29 (d, 1H), 7.85 (d, 1H), 7.60-7.67 (m, 2H), 4.94 (s,2H), 2.67 (s, 3H). LCMS (method A): [MH]⁺=339, t_(R)=4.88 min.

(E)-1-(3-((5,7-difluoroquinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanoneoxime (Example 78)

1-[3-(5,7-Difluoro-quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]ethanone(78.4, 320 mg, 0.943 mmol) and hydroxylamine hydrochloride (131 mg,1.886 mmol) in methanol (30 mL) was stirred at it overnight. LCMS showedthe reaction was complete. The reaction solution was tuned with 1N NaOHaqueous solution until pH 8-9, solvent was evaporated, and the residuewas purified by column chromatography to afford 310 mg (93% yield) ofthe title compound as a yellow solid. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm12.29 (s, 1H), 8.99 (dd, 1H), 8.49 (d, 1H), 8.24 (d, 1H), 7.74 (d, 2H),7.63 (dd, 1H), 4.76 (s, 2H), 2.15 (s, 3H). LCMS (method A): [MH]⁺=355,t_(R)=5.32 min.

Example 79(E)-1-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)ethanoneO-2-hydroxyethyl oxime

6-bromo-1,2,4-triazin-3-amine (79.1)

A mixture of 3-amino-1,2,4-triazine (50.0 g, 521 mmol) in water (6000mL) was cooled to 0-5° C. The bromine (70 mL, 1.30 mmol) was addeddropwise to the reaction mixture for 1 h. Then the mixture was stirredovernight at 0-10° C. A saturated aqueous Na₂SO₃ solution was added tothe reaction and the mixture was neutralized to pH=12 with a 6 N aqueousNaOH solution. The mixture was extracted with dichloromethane, driedover Na₂SO₄. The solvent was removed in vacuo to afford 50.0 g (54%) ofthe title compound as a yellow solid. ¹H-NMR (400 MHz, d₆-DMSO) δ ppm8.40 (s, 1H), 7.47 (s, 2H). LCMS (method B): [MH]⁺=175/177, t_(R)=0.328min.

6-(1-ethoxyvinyl)-1,2,4-triazin-3-amine (79.2)

A solution of 6-bromo-1,2,4-triazin-3-amine (780 mg, 4.46 mmol) inN,N-dimethylformamide (50 mL) was treated withtetrakis(triphenylphosphine) palladium (0) (258 mg, 0.22 mmol),N,N-diisopropylethyl amine (2284 mg, 11.14 mmol), lithium chloride (661mg, 15.6 mmol), and vinyltri-n-butyltin (2093 mg, 5.79 mmol), and thereaction was heated at 120° C. for 2 h. The reaction mixture was cooledto room temperature and concentrated the solvent in vacuo. The residuewas diluted with dichloromethane and washed with aqueous KF solution.The crude product was purified by flash chromatography in silica geleluting with a ethyl acetate/hexane gradient to afford 380 mg (51%) ofthe title compound as a yellow solid. ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.48(s, 1H), 5.41-5.39 (m, 3H), 4.36 (s, 1H), 3.98 (q, 2H), 1.43 (t, 2H).

6-((2-(2-methyl-1,3-dioxolan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)methyl)quinoline(79.3)

A solution of 6-(1-ethoxyvinyl)-1,2,4-triazin-3-amine (120 mg, 0.72mmol), 2-chloro-3-(quinolin-3-yl)propanal (317 mg, 1.44 mmol) inethylene glycol (8 mL) was stirred at 140° C. for 2 h. The reactionmixture was cooled to room temperature, neutralized with saturatedaqueous Na₂CO₃ solution and diluted with water, extracted with ethylacetate, dried over Na₂SO₄. The solvent was removed in vacuo and theresidue was purified by flash chromatography in silica gel eluting witha ethyl acetate/hexane gradient to afford 135 mg (54%) of the titlecompound as yellow solid. LCMS (method B): [MH]⁺=348, t_(R)=2.03 min.

1-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)ethanone(79.4)

A solution of6-((2-(2-methyl-1,3-dioxolan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)methyl)quinoline(130 mg, 0.37 mmol) in 3 N HCl (5 mL) was stirred at 90° C. for 0.5 h.The reaction mixture was cooled to room temperature, neutralized withsaturated aqueous Na₂CO₃ solution, extracted with ethyl acetate, driedover Na₂SO₄. The solvent was removed in vacuo to afford 85 mg (75%) ofthe title compound as yellow solid. ¹H-NMR (400 MHz, CDCl₃) δ ppm 9.06(s, 1H), 8.91 (d, 1H), 8.12 (t, 2H), 8.04 (s, 1H), 7.74-7.71 (m, 2H),7.48-7.39 (m, 1H), 4.60 (s, 2H), 2.70 (s, 3H). LCMS (method B):[MH]⁺=304, t_(R)=1.81 min.

(E)-1-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)ethanoneO-2-hydroxyethyl oxime (Example 79)

A solution of1-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)ethanone (40mg, 0.13 mmol), 2-(aminooxy)ethanol hydrochloride (30 mg, 0.26 mmol) andHCl (4 N in 1,4-dioxane, 0.1 mL) in methanol (5 mL) was stirred at roomtemperature for 48 h. The reaction mixture was neutralized withsaturated aqueous NaHCO₃ solution and diluted with water, extracted withdichloromethane, dried over Na₂SO₄. The solvent was removed in vacuo andthe residue was purified by flash chromatography in silica gel elutingwith a ethyl acetate/methanol gradient to afford 35 mg (74%) of thetitle compound as yellow solid. ¹H-NMR (400 MHz, d₆-DMSO) δ ppm 8.94 (s,1H), 8.84 (d, 1H), 8.28 (d, 1H), 7.97-7.91 (m, 3H), 7.77 (d, 1H), 7.49(dd, 1H), 4.77 (t, 1H), 4.56 (s, 2H), 4.30-4.27 (m, 2H), 3.71-3.70 (m,2H), 2.25 (s, 3H). LCMS (method B): [MH]⁺=363, t_(R)=2.08 min.

Example 80(E)-1-(7-(Quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)ethanoneoxime

The title compound was prepared using the same procedure as described inthe synthesis of example 79. ¹H-NMR (400 MHz, d₆-DMSO) 3 ppm 12.27 (s,1H), 8.93 (s, 1H), 8.85 (s, 1H), 8.29 (d, 1H), 7.95 (d, 1H), 7.90 (d,2H), 7.77 (d, 1H), 7.50 (s, 1H), 4.56 (s, 2H), 2.21 (s, 3H). LCMS(method B): [MH]⁺=319, t_(R)=2.065 min.

Example 811-(3-Quinolin-6-ylmethyl-imidazo[1,2-a]pyrimidin-6-yl)-ethanone oxime

1-(3-Quinolin-6-ylmethyl-imidazo[1,2-a]pyrimidin-6-yl)-ethanone oximecan be generated from1-(3-quinolin-6-ylmethyl-imidazo[1,2-a]pyrimidin-6-yl)-ethanone(intermediate W) and hydroxyamine.

Example 82

1-(3-Quinolin-6-ylmethyl-imidazo[1,2-a]pyrimidin-6-yl)-ethanoneO-(2-hydroxy-ethyl)-oxime can be generated from1-(3-quinolin-6-ylmethyl-imidazo[1,2-a]pyrimidin-6-yl)-ethanone(intermediate W) and 2-Aminooxy-ethanol.

In another embodiment of the invention, there is provided a crystallineform of the compound of Example 53S. Such forms provide a significantimprovement in processing properties compared to the amorphous form, andprovide improvements in thermodynamic stability and hygroscopicity.Furthermore, the crystallization process provided aids in removingimpurities.

Example 1 Amorphous Form of the Compound of Example 53S

The amorphous form of Ex 53S was obtained using the following methods:

1A. Room Temperature Slow Evaporation Crystallization Method

Solvents: Acetone, isopentyl alcohol, methylene chloride, methylethylketone, n-propanol, tetrahydrofuran, Pentanol, EtOH/Water 1:1.

Procedure:

(1) About 2 mg of drug substance was dissolved in 0.2 ml solvent.

(2) Solvent was allowed to evaporate slowly at room temperature

(3) The solid product was dried in vacuum oven at 40° C. overnight andanalysed by XRPD.

IB. Anti-Solvent Method:

(1) About 2 mg of drug substance was dissolved in 0.2 ml solvent.

(2) Anti-solvent was added to precipitate the compound.

(3) The vial was refrigerated overnight.

(4) Solvent was allowed to evaporate slowly

(5) The solid product was dried in vacuum oven at 40° C. overnight andanalysed by XRPD.

Solvent Anti-solvent acetone water isopropanol hexane2-methyl-1-propanol water n-Butanol water Pentanol water dioxane water

IC. Slurry Method:

Solvent: ethyl acetate

(1) About 2 mg of drug substance was suspended in 0.2 ml solvent.

(2) Solvent was allowed to evaporate slowly at room temperature

(3) The solid product was dried in vacuum oven at 40° C. overnight andanalysed by XRPD.

Example 2 Crystalline Form I of the Compound of Example 53S

A crystalline form I of the compound of Example 53S was obtained usingdifferent crystallisation methods:

2A. Room Temperature Slow Evaporation Crystallization Method

Solvents: Acetonotrile, ethanol, ether, ethyl acetate, methanol, methyltert-butyl ether, butyl acetate, 2-methyl-1-propanol, toluene, water,95% EtOH.

(1) About 2 mg of drug substance was dissolved in 0.2 ml solvent.

(2) Solvent was allowed to evaporate slowly at room temperature

(3) The solid product was dried in the vacuum oven at 40° C. overnightand analysed by XRPD. Scale-up samples were further characterised usingXRPD, DSC and TGA. Ex 53S crystalline form I was obtained.

2B. Anti-Solvent Method:

(1) About 2 mg of drug substance was dissolved in 0.2 ml solvent.

(2) Anti-solvent was added to precipitate the compound.

(3) The vial was refrigeratated overnight.

(4) Solvent was allowed to evaporate slowly

(5) The solid product was dried in the vacuum oven at 40° C. overnightand analysed by XRPD. Scale-up samples were characterized using XRPD,DSC and TGA.

Solvent Anti-solvent acetonitrile water methanol hexane ethanol waterTHF hexane acetone ether

Example 53S crystalline form I was obtained.

2C. Slurry Method

Solvents: ether, hexane, methyl tert-butyl ether, Butyl acetate,toluene, Water, Pentane.

(1) About 2 mg of drug substance was suspended in 0.2 ml solvent andequilibrated for 24 hours.

(2) Solvent was allowed to evaporate slowly at room temperature

(3) The solid product was dried in the vacuum oven at 40° C. overnightand investigated by XRPD. Scale-up samples were further characterizedusing XRPD, DSC and TGA. Example 53S crystalline form I was obtained.

TABLE 1 XRPD data of Example 53S crystalline form I Intensity Angle dvalue % 2-Theta ° Angstrom % 10.6 8.34 86 14.2 6.24 100 15.6 5.66 27.517.1 5.20 59 17.5 5.05 73.1 19.3 4.60 53.3 20.9 4.25 56.1 21.6 4.10 17.222.6 3.93 46.2 23.5 3.79 43 23.9 3.72 71.9 24.8 3.59 43.5 25.3 3.51 4626.2 3.40 25.5 26.7 3.34 32.4 27.3 3.27 26.6 28.7 3.11 29.6 30.9 2.8929.8 31.8 2.81 29.8 33.0 2.71 21.3 37.0 2.43 18.1

In a particular embodiment of the invention, there is provided acrystalline form of the compound of Example 53S comprising the followingpeaks:

Angle d value 2-Theta ° Angstrom 10.6 8.34 14.2 6.24 17.1 5.20 17.5 5.0523.9 3.72

Example 3 Crystalline Form II of the Compound of Example 53S

A crystalline form II of the compound of Example 53S was obtained usingdifferent crystallization methods

3A. Room Temperature Slow Evaporation Crystallization Method:

Solvents: cyclohexane, hexane, methanol, n-butanol, pentane.

(1) About 2 mg of drug substance was dissolved in 0.2 ml solvent.

(2) Solvent was allowed to evaporate slowly at room temperature

(3) The solid product was dried in the vacuum oven at 40° C. overnightand analysed by XRPD. Scale-up samples were further characterized usingXRPD, DSC and TGA. Example 53S crystalline form II was obtained.

3B. Anti-Solvent Method:

(1) About 2 mg of drug substance was dissolved in 0.2 ml methylenechloride.

(2) Anti-solvent hexane was added to precipitate compound.

(3) The vial was refrigerated overnight

(4) Solvent was allowed to evaporate slowly

(5) The solid product was dried in the vacuum oven at 40° C. overnightand analysed by XRPD. Scale-up samples were further characterized usingXRPD, DSC and TGA. Example 53S crystalline form II was obtained.

3C. Slurry Method

Solvents: cyclohexane.

(1) About 2 mg of drug substance was suspended in 0.2 ml solvent.

(2) Solvent was allowed to evaporate slowly at room temperature

(3) The solid product was dried in the vacuum oven at 40° C. overnightand analysed by XRPD. Scale-up samples were further characterized usingXRPD, DSC and TGA. Ex 53S crystalline form II was obtained.

TABLE 2 XRPD data of Exampe 53S crystalline form II Intensity Angle dvalue % 2-Theta ° Angstrom % 8.7 10.16 19.9 9.0 9.80 40.3 10.0 8.83 49.110.7 8.29 28.3 11.4 7.73 27 13.2 6.70 73.3 14.2 6.21 39.2 15.2 5.82 84.715.7 5.63 17.9 17.1 5.19 100 17.7 5.02 93.5 18.6 4.78 27.8 19.8 4.4935.9 20.3 4.37 55.6 20.9 4.24 32.7 22.4 3.97 26.4 22.8 3.90 27.1 23.53.78 28.9 24.5 3.63 30.4 24.8 3.59 33.3 25.4 3.51 36.2 26.1 3.41 51.427.0 3.30 32.3 28.7 3.11 28.7 29.9 2.99 21.5 32.3 2.77 20.2 34.4 2.6027.8 35.8 2.51 22.3 37.2 2.42 17.4 38.8 2.32 14.5 41.2 2.19 13.6 43.32.09 16.2

In a particular embodiment of the invention, there is provided acrystalline form of the compound of Example 53S comprising the followingpeaks:

Angle d value 2-Theta ° Angstrom 13.2 6.70 15.2 5.82 17.1 5.19 17.7 5.0220.3 4.37Instrument name: X-ray Diffractometer

Model: D8 Discover Manufacturer: Bruker AXS GMBH Wavelength: 1.54184 Å(Cu)

Generator setting: 40.00 KV, 40.00 mA

Monochromator Detector: HI-STAR

Frame Size: 1024 pixels, 107.79 mm

Experiment Method:

2-Theta start: 5.0 degree2-Theta end: 45.0 degreePixel overlap: 20%Integration stepsize: 0.02 degreeScan time: 120 seconds

Temperature: Room Temperature C-Met Enzyme Assay

A number of compounds of the present invention were assayed in anantibody based kinase phosphorylation assay as follows.

EPK c-MET Profiling Assay:

The EPK kinase assay for c-MET receptor tyrosine kinase was developed,using the purified recombinant GST-fusion protein, containing thecytoplasmic domain of the enzyme. GST-c-MET(969-1390) was purified byaffinity chromatography.

The kinase assay is based on the LanthaScreen™ technology. LanthaScreen™is the detection of Time-Resolved Fluorescence Resonance Energy Transfer(TR-FRET) using lanthanide chelates to measure interactions betweenvarious binding partners. In a TR-FRET kinase assay, a long-lifetimelanthanide donor species is conjugated to an antibody that specificallybinds to a phosphorylated product of a kinase reaction that is labeledwith a suitable acceptor fluorophore. This antibody-mediated interactionbrings the lanthanide donor and the acceptor into proximity such thatresonance energy transfer can take place, resulting in a detectableincrease in the FRET signal.

The kinase reactions were performed in 384 well microtiter plates in atotal reaction volume of 10.05 μL. The assay plates were prepared with0.05 μL per well of test compound in the appropriate test concentration,as described under “preparation of compound dilutions”. The reactionswere started by combining 5 μL of ATP solution with 5 μL ofenzyme-substrate mix (consisting of kinase and substrate). The finalconcentrations in the kinase reactions were 25 mM Tris/HCl, 1 mM DTT,0.025% Tween20, 10 μM sodium orthovanadate, 0.25% BSA, 0.5% DMSO, 10 mMMgCl₂, 3 mM MnCl₂, 2 μM ATP, 50 nM Fluorescein-PolyEAY, and 0.3 nMenzyme.

The reactions were incubated for 60 minutes at room temperature andstopped by adding 5 μL of stop buffer (50 mM EDTA, 0.04% NP40, 20 mMTris/HCl).

Subsequently 5 μL of detection mix (50 mM Tris/HCl, 2 mM DTT, 0.05%Tween20, 20 μM sodium orthovanadate, 1% BSA, 1 nM Tb-PY20 antibody) wereadded to the stopped reactions. After 45 minutes incubation in dark atroom temperature, the plates were measured in a Perkinelmer Envisionfluorescence reader. The effect of compound on the enzymatic activitywas in all assays obtained from the linear progress curves anddetermined from one reading (end point measurement).

Results are summarized in the Table below. “Active” compounds of theinvention have an IC50 in this enzyme assay of less than 5000 nM,preferably less than 1000 nM, more preferably less than 200 nM and mostpreferably less than 10 nM.

GTL16 Cell Viability Assay:

GTL16 cell line is derived from a gastric cancer patient. GTL16expresses high level of c-Met receptor tyrosine kinase due to the geneamplification. The growth of GTL16 is highly dependent on c-Met kinaseactivity; hence it is used as a cell base assay to monitor the cellularactivity of the c-Met kinase inhibitors.

GTL16 cells were seeded in DMEM medium with 10% FBS and 1% Pene. &Strep. at 5000 cells/well/90 μL in 96 well plate and incubated overnightfor attachment at 37° C. in 5% CO₂ incubator. 10-fold serials dilutionsof compounds were added to the cell as 10 μL/well. The final assayvolume was 100 μl/well. The assay plates were incubated at 37° C. in 5%CO₂ incubator for 24 hours. The viability of cells was measured usingthe CellTiter Glo (Cat# G7573 Promega) according to the protocolsuggested by the vender. Briefly, the plates were cooled at roomtemperature for 10 mins and 100 μl of CellTiter Glo reagent was addedinto each well. Plates were shaken for 10 mins. The chemiluminescentlight unit was read in Envision from Perkin Elmer. All the tests wererun at triplicates. The IC₅₀ was calculated using Spotfire software.

TABLE 1 Inhibitory Activity of Compounds Example c-Met biochem number(IC₅₀ nM)  1 36  2 10  3 8  4 73  5 27  6 5.5  7A 59  7B 59  8 1.8  96.7 10 24 11-S 6 11-R 117 12-S 2.5 12-R 100 13 51 14 55 15 2.8 16 7.3 1746 18 29 19 5.4 20 29 21 5.1 22 2.4 23 2.2 24 3 25 34 26A 20 26B 9 27440 28 590 29 360 30 160 31 28 32 32.5 33 70 34 12 35 60 36 35 37A 16.537B 3.9 38 3.6 39-R 444 39-S 19 40 68 41 10 42 7 43 29 44 13 45 34 46120 47 3600 48 380 49 440 50 1.5 51-S 2.8 51-R 460 52 11 53-S 3.5 53-R368 54 3 55 3.8 56 2.5 57 28 58 14 59 153 60 156 61 83 62-S 21 62-R 13763 6 64 18 65 15 66 42 67 8 68-S 13 68-R 223 69 4.7 70 127 71 7 72 11 7312 74 17 75-S 1.2 75-R 19 76-S 24 76-R 1064 77-S 0.48 77-R 20 78 0.4 797.1 80 3.8

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein Y is C or N; X isN; B is CH or N; A is a ring selected from Ai and Aiii;

R¹ is a group i:

wherein R⁵ is heteroaryl¹, R⁶ is hydrogen, OH, methyl or halo; R⁷ ishydrogen, halo, or (C₁-C₃)alkyl, wherein said (C₁-C₃)alkyl is optionallysubstituted by one or more substituents independently selected from OHand halo; or R⁶ and R⁷, together with the carbon to which they areattached, form cyclopropyl; R² is hydrogen, NH₂, or (C₁-C₄)alkyl,wherein said (C₁-C₄)alkyl is optionally substituted by one or moresubstituents independently selected from OH, NH₃ and halo; and R³ is(C₁-C₆)alkyl, wherein said (C₁-C₆)alkyl is optionally substituted by oneor more substituents independently selected from halo, hydroxy and(C₁-C₃)alkoxy; heterocyclyl¹; phenyl, wherein said phenyl is optionallysubstituted by one or more substituents independently selected fromhalo, hydroxy, (C₁-C₃)alkyl and (C₁-C₃)alkoxy, wherein said (C₁-C₃)alkyland (C₁-C₃)alkoxy are each optionally substituted by one or more halosubstituents; —CH₂-heterocyclyl¹; —CH₂-phenyl, wherein the phenyl ofsaid —CH₂-phenyl is optionally substituted by one or more substituentsindependently selected from halo, hydroxy, (C₁-C₃)alkyl and(C₁-C₃)alkoxy, wherein said (C₁-C₃)alkyl and (C₁-C₃)alkoxy are eachoptionally substituted by one or more halo substituents;(C₁-C₄)alkylCO₂(C₁-C₂)alkyl; (C₀-C₄)alkylCONH₂; (C₁-C₄)alkylNH₂;(C₁-C₄)alkylNHCONH₂; (C₁-C₄)alkylCO₂H; (C₁-C₄)alkylNHCO₂CH₃;—(C₀-C₄)alkyl(C₃-C₆)cycloalkyl or —(C₀-C₄)alkyl(C₄-C₆)cycloalkenyl; orhydrogen; heteroaryl¹ is a 9- or 10-membered, unsaturated or partiallyunsaturated bicyclic group comprising 1, 2, 3 or 4 ring heteroatomsindependently selected from N, O and S, wherein the total number of ringS atoms does not exceed 1, and the total number of ring O atoms does notexceed 1, and wherein heteroaryl¹ is optionally substituted by one ormore substituents independently selected from: halo; OH; (C₁-C₃)alkyl,said (C₁-C₃)alkyl being optionally substituted by one or moresubstituents independently selected from OH and halo; heterocyclyl²; and—C(CH₃)═NO(C₁-C₃)alkyl, wherein the (C₁-C₃)alkyl of saidC(CH₃)═NO(C₁-C₃)alkyl is optionally substituted by one or moresubstituents independently selected from OH and halo; heterocyclyl¹ is a4, 5 or 6 membered saturated or partially unsaturated monocyclic groupcomprising 1 or 2 ring heteroatoms independently selected from N, O andS, and wherein heterocyclyl¹ is optionally substituted by CONH₂ or(C₁-C₃)alkyl; and heterocyclyl² is a 5 or 6 membered saturated,unsaturated or partially unsaturated monocyclic group comprising 1, 2 or3 ring heteroatoms independently selected from N, O and S, wherein thetotal number of ring S atoms does not exceed 1, and the total number ofring O atoms does not exceed 1, and heterocyclyl² is optionallysubstituted by (C₁-C₃)alkyl.
 2. The compound or pharmaceuticallyacceptable salt thereof as claimed in claim 1 wherein R⁵ is heteroaryl³,and heteroaryl³ is a 9- or 10-membered, unsaturated or partiallyunsaturated bicyclic group comprising 1 or 2 ring N heteroatoms, saidheteroaryl³ being optionally substituted by one or more substituentsindependently selected from: halo; OH; (C₁-C₃)alkyl, wherein said(C₁-C₃)alkyl is optionally substituted by one or more substituentsindependently selected from OH and halo; heterocyclyl²; and—C(CH₃)═NO(C₁-C₃)alkyl, wherein the (C₁-C₃)alkyl of saidC(CH₃)═NO(C₁-C₃)alkyl is optionally substituted by one or moresubstituents independently selected from OH and halo.
 3. The compound orpharmaceutically acceptable salt thereof as claimed in claim 2, whereinR⁵ is indazolyl or quinolinyl, each optionally substituted by one ormore substituents independently selected from halo, (C₁-C₃)alkyl,4-methylpiperazin-1-yl and ethanone O-(2-hydroxyethyl)oxime.
 4. Thecompound or pharmaceutically acceptable salt thereof as claimed in claim3, wherein R⁵ is indazolyl optionally substituted by one, two or threesubstituents independently selected from methyl and fluoro, or R⁵ isquinolinyl optionally substituted by one or two fluoro substituents. 5.The compound or pharmaceutically acceptable salt thereof as claimed inclaim 1, wherein R⁶ is hydrogen.
 6. The compound or pharmaceuticallyacceptable salt thereof as claimed in claim 1, wherein R⁷ is hydrogen ormethyl.
 7. The compound or pharmaceutically acceptable salt thereof asclaimed in claim 1, wherein R² is methyl.
 8. The compound orpharmaceutically acceptable salt thereof as claimed in claim 1, whereinR³ is selected from: (C₁-C₄)alkyl, wherein said (C₁-C₄)alkyl isoptionally substituted by one or more substituents independentlyselected from halo, hydroxy and methoxy; pyrrolidinyl, optionallysubstituted by CONH₂; piperidinyl; phenyl, wherein said phenyl isoptionally substituted by one or more substituents independentlyselected from halo, hydroxy, (C₁-C₃)alkyl and (C₁-C₃)alkoxy, whereinsaid (C₁-C₃)alkyl and (C₁-C₃)alkoxy are each optionally substituted byone or more halo substituents; —CH₂-pyrrolidinyl, wherein saidpyrrolidinyl is optionally substituted by CONH₂; —CH₂-piperidinyl;—CH₂-phenyl, wherein the phenyl of said —CH₂-phenyl is optionallysubstituted by one or more substituents independently selected fromhalo, methyl and methoxy, wherein said methyl is optionally substitutedby one, two or three halo substituents; (C₁-C₂)alkylCO₂(C₁-C₂)alkyl;(C₀-C₂)alkylCONH₂; (C₂-C₄)alkylNH₂; (C₁-C₂)alkylNHCONH₂;(C₁-C₂)alkylCO₂H; oxetanyl; (C₁-C₂)alkylNHCO₂CH₃;—CH₂—(C₃-C₆)cycloalkyl; and hydrogen.
 9. The compound orpharmaceutically acceptable salt thereof as claimed in claim 9, whereinR³ is ethyl, methyl, 2-hydroxyethyl, 1,3-dihydroxypropan-2-yl-,2,3-dihydroxypropyl-, 2-hydroxy-1,1-dimethyl-ethyl-,2-hydroxy-2-methyl-propyl-, pyrrolidin-3-yl-,-3-pyrrolidine-1-carboxamide, hydrogen, benzyl, 4-methoxybenzyl-,piperidin-4-yl-, piperidin-4-ylmethyl-, —CH₂CO₂CH₃, —CH₂CONH₂,2-aminoethyl-, 1-hydroxypropan-2-yl-, —CH₂CH₂NHCO₂CH₃, —CH₂CH₂NHCONH₂;3-trifluoromethylphenyl-, phenyl, 2-fluoroethyl-, 3-hydroxypropyl,2-methoxyethyl, 4-hydroxybutyl, 4-fluorobutyl, CONH₂,1-hydroxy-2-methylpropan-2-yl, oxetan-3-yl, —CH₂CO₂H, cyclopropylmethyl,or hydrogen.
 10. The compound or pharmaceutically acceptable saltthereof as claimed in claim 10, wherein R³ is hydroxyethyl or hydrogen.11. The compound or pharmaceutically acceptable salt thereof as claimedin claim 1, wherein when R¹ is i and R⁶ and R⁷ are not both hydrogen,the compound of formula (I) is the (S) enantiomer.
 12. A compound, orpharmaceutically acceptable salt thereof, selected from:


13. A compound, or pharmaceutically acceptable salt thereof, selectedfrom:


14. A pharmaceutical composition comprising a compound of formula (I) asclaimed in claim 1, or a pharmaceutically acceptable salt thereof, andat least one pharmaceutically acceptable carrier or diluents andoptionally one or more further therapeutic agents.
 15. A compound offormula (I) or a pharmaceutically acceptable salt thereof, as claimed inclaim 1, in combination with one or more additional therapeuticallyactive agents.
 16. A method of treating a c-Met related disorder orcondition selected from papillary renal cell carcinoma, hepatocellularcarcinoma, gastric cancer and cancers of the lung, head and neck, whichinvolves administering to a subject in need thereof an effective amountof a compound of formula (I) or a pharmaceutically acceptable saltthereof.